Obesity, kidney dysfunction and hypertension: mechanistic links

In the paper

“We showed that MR blockade markedly attenuated glomerular hyperfiltration in obese dogs fed an HFD47.”

What the sources say

• Supported

  The Discussion states that eplerenone markedly attenuated glomerular hyperfiltration during the development of obesity in dogs fed a high-fat diet. The section “Aldosterone Antagonism Attenuates Glomerular Hyperfiltration in Obesity” reiterates that finding. (LLM, conf=0.94)

  cites [47] de Paula, R. B., da Silva, A. A. & Hall, J. E. Aldosterone antagonism attenuates obesity-induced hypertension and glomerular hyperfiltration. Hypertension 43, 41–47 (2004). source

In the paper

“Excessive RSF and PRF may also cause lipotoxicity owing to the accumulation of intracellular triglycerides and toxic metabolites such as ceramides57,58.”

What the sources say

• Partly supported

  The Discussion (page unavailable) says intracellular lipid accumulation can cause lipotoxicity, and the paper reports increased intracellular triglycerides in mouse proximal tubule cells. It does not link renal sinus or perirenal fat to that process, or identify ceramides as the toxic metabolites involved. (LLM, conf=0.88)

  cites [57] Adeosun, S. O. et al. Loss of biliverdin reductase-A promotes lipid accumulation and lipotoxicity in mouse proximal tubule cells. Am. J. Physiol. Renal Physiol. 315, F323–F331 (2018). sourceExperimental — accuracy not yet measured
• Partly supported

  The paper’s “Can Ectopic Lipid Deposition Injure Normal Tissues?” section describes lipotoxic injury associated with intracellular lipid accumulation in cardiomyocytes and ceramide formation in pancreatic islets. It does not establish this mechanism for renal sinus or perirenal fat. The “Protective Role of Obesity” section also describes stored neutral fat as potentially harmless, so the paper does not clearly support treating accumulated triglycerides themselves as toxic. (LLM, conf=0.87)

  cites [58] Unger, R. H. & Scherer, P. E. Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity. Trends Endocrinol. Metab. 21, 345–352 (2010). sourceExperimental — accuracy not yet measured

In the paper

“The landmark PATHWAY-2 trial85,86 clearly established that the MR antagonist spironolactone is effective for treating patients with resistant hypertension who are usually overweight or obese and already on at least three antihypertensive drugs87.”

What the sources say

• Partly supported

  The Introduction says spironolactone lowered blood pressure more effectively than the comparators in PATHWAY-2 and defines resistant hypertension as uncontrolled despite at least three blood-pressure drugs. The Methods confirm participants were taking three drugs. The Results table reports bodyweight but not BMI or the proportion overweight or obese, so the claim that patients were usually overweight or obese is not established by our copy. (LLM, conf=0.85)

  cites [85] Williams, B. et al. Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies. Lancet Diabetes Endocrinol. 6, 464–475 (2018). sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion reports that spironolactone was the most effective blood-pressure-lowering treatment in PATHWAY-2, and Methods > Study design and participants says patients entered despite treatment with three antihypertensive drugs. The Introduction associates resistant hypertension with obesity, but the passages found do not establish that patients were usually overweight or obese. (LLM, conf=0.83)

  cites [86] Williams, B. et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 386, 2059–2068 (2015). sourceExperimental — accuracy not yet measured
• Partly supported

  The Pharmacological Treatment of RH section says mineralocorticoid receptor blockade improves blood pressure in resistant hypertension and discusses spironolactone as a fourth drug. General Principles says patients should already be taking three antihypertensive agents. Patient Characteristics says obesity is more common in resistant hypertension than in non-resistant hypertension, but it does not establish that these patients are usually overweight or obese. (LLM, conf=0.84)

  cites [87] Carey, R. M. et al. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association. Hypertension 72, e53–e90 (2018). sourceExperimental — accuracy not yet measured

In the paper

“Leptin infusion in ob/ob mice raised their BP despite causing significant weight loss131.”

What the sources say

• Supported

  In “Leptin injection experiments” (p. 1248), the paper reports that three days of leptin infusion significantly reduced body weight in ob/ob mice relative to vehicle treatment. It also reports that leptin raised their systolic blood pressure by as much as 25 mmHg, while blood pressure was unchanged in vehicle-treated mice. (LLM, conf=0.94)

  cites [131] Aizawa-Abe, M. et al. Pathophysiological role of leptin in obesity-related hypertension. J. Clin. Invest. 105, 1243–1252 (2000). source

In the paper

“Plasma leptin concentration is highly correlated with SNA activity123, and acute leptin infusions increase SNA in the brown adipose tissue, adrenal glands and kidneys of rodents124.”

What the sources say

• Supported

  The Discussion states that leptin infusion increased sympathetic nerve activity to brown adipose tissue, kidney, and adrenal gland in lean Sprague-Dawley rats. The results sections report increases in all three during intravenous infusion, supporting the claim about acute infusions in rodents. (LLM, conf=0.94)

  cites [124] Haynes, W. G., Morgan, D. A., Walsh, S. A., Mark, A. L. & Sivitz, W. I. Receptor-mediated regional sympathetic nerve activation by leptin. J. Clin. Invest. 100, 270–278 (1997). source

In the paper

“Obesity is also associated with a heightened central chemoreflex response to hypercapnia in the absence of coexisting disease182,183.”

What the sources say

• ?Could not verify

  The chemoreflexes section says central chemoreceptors respond mainly to hypercapnia, but does not compare responses in people with and without obesity. The Relationship with obesity section discusses sympathetic activity in OSA and suggests its enhanced chemoreflex mechanism is unlikely to be due to obesity alone; it does not address central chemoreflex responses to hypercapnia in people without coexisting disease. Searches for obesity, central chemosensitivity, and hypercapnic response found no passage establishing the claim. (LLM, conf=0.72)

  cites [182] Mansukhani, M. P., Kara, T., Caples, S. M. & Somers, V. K. Chemoreflexes, sleep apnea, and sympathetic dysregulation. Curr. Hypertens. Rep. 16, 476 (2014). sourceExperimental — accuracy not yet measured
• Supported

  The “Chemoreflexes in Obesity” section directly states that studies of obese humans free of coexisting disease show a heightened central chemoreflex response to hypercapnia. This matches the attributed claim. (LLM, conf=0.95)

  cites [183] Mansukhani, M. P., Wang, S. & Somers, V. K. Chemoreflex physiology and implications for sleep apnoea: insights from studies in humans. Exp. Physiol. 100, 130–135 (2015). source

In the paper

“This procedure did not blunt the rise in BP during development of obesity-induced hypertension, indicating that the BP effects of RDN are due to ablation of renal sympathetic efferent fibres rather than sensory afferent nerves.”

What the sources say

• Not checked yetcites [173] Zappe, D. H. et al. Role of renal afferent nerves in obesity-induced hypertension. Am. J. Hypertens. 9, 20A (1996). source

In the paper

“A nearly linear relationship exists between BP and indices of obesity, including BMI, in every population examined, including white, black, Hispanic and Asian populations6,25.”

What the sources say

• Not checked yetcites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). source
• Not checked yetcites [25] Jones, D. W., Kim, J. S., Andrew, M. E., Kim, S. J. & Hong, Y. P. Body mass index and blood pressure in Korean men and women: the Korean National Blood Pressure Survey. J. Hypertens. 12, 1433–1437 (1994). source

In the paper

“A study in individuals aged 25–74 years reported that a 1 s.d. increase in BMI over a 5-year period led to a 30% increase in risk of hypertension compared with people whose weight did not change28.”

What the sources say

• Not checked yetcites [28] Nyamdorj, R. et al. Comparison of body mass index with waist circumference, waist-to-hip ratio, and waist-to-stature ratio as a predictor of hypertension incidence in Mauritius. J. Hypertens. 26, 866–870 (2008). source

In the paper

“Other cardiovascular, renal, endocrine and sympathetic nervous system (SNS) changes that are associated with obesity caused by an HFD in dogs and rabbits closely mimic those found in people who are obese6.”

What the sources say

• Not checked yetcites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). source

In the paper

“Prolonged obesity and progressive renal injury often lead to the development of treatment-resistant hypertension.”

In the paper

“Studies in primary care settings report that 60–76% of patients who are overweight or obese have hypertension, defined as BP >140/90 mmHg 26.”

What the sources say

• Not checked yetcites [26] Bramlage, P. et al. Hypertension in overweight and obese primary care patients is highly prevalent and poorly controlled. Am. J. Hypertens. 17, 904–910 (2004). source

In the paper

“Several haemodynamic, renal and neurohormonal changes occur during the development of obesity-induced hypertension in humans and in experimental animal models of obesity caused by overfeeding (TABLE 1).”

In the paper

“Thus, the risk of developing hypertension increases with obesity duration.”

In the paper

“In the Johns Hopkins Precursors Study, obesity in young adults conferred a threefold greater risk of hypertension after 46 years of follow-up, even after accounting for changes in lifestyle factors over the life course30.”

What the sources say

• Not checked yetcites [30] Shihab, H. M. et al. Body mass index and risk of incident hypertension over the life course: the Johns Hopkins Precursors Study. Circulation 126, 2983–2989 (2012). source

In the paper

“Evidence suggests that excessive adipose deposition around the kidneys (for example, renal sinus fat (RSF) and perirenal fat (PRF)) may be associated with hypertension even after adjustment for traditional risk factors, including overall adiposity and BMI6,19–21.”

What the sources say

• Not checked yetcites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). source
• Not checked yetcites [19] Chughtai, H. L. et al. Renal sinus fat and poor blood pressure control in middle-aged and elderly individuals at risk for cardiovascular events. Hypertension 56, 901–906 (2010). source
• Not checked yetcites [20] Foster, M. C. et al. Fatty kidney, hypertension, and chronic kidney disease: the Framingham Heart Study. Hypertension 58, 784–790 (2011). source
• Not checked yetcites [21] Chandra, A. et al. The relationship of body mass and fat distribution with incident hypertension: observations from the dallas heart study. J. Am. Coll. Cardiol. 64, 997–1002 (2014). source

In the paper

“people who are obese and considered to be normotensive often experience a reduction in BP when they reduce their overall adiposity by losing weight35.”

What the sources say

• Not checked yetcites [35] Hall, J. E., Crook, E. D., Jones, D. W., Wofford, M. R. & Dubbert, P. M. Mechanisms of obesity-associated cardiovascular and renal disease. Am. J. Med. Sci. 324, 127–137 (2002). source

In the paper

“Excessive adiposity raises blood pressure and accounts for 65–75% of primary hypertension”

In the paper

“Epidemiology studies indicate that 65–75% of primary (essential) hypertension is due to overweight or obesity7.”

What the sources say

• Not checked yetcites [7] Garrison, R. J., Kannel, W. B., Stokes, J. III & Castelli, W. P. Incidence and precursors of hypertension in young adults: the Framingham Offspring Study. Prev. Med. 16, 235–251 (1987). source

In the paper

“In obesity, abnormal kidney function and associated increases in tubular sodium reabsorption initiate hypertension”

In the paper

“However, body weight remained the strongest predictor of BP in Pima Indians34.”

What the sources say

• Not checked yetcites [34] de Courten, M. P., Pettitt, D. J. & Knowler, W. C. Hypertension in Pima Indians: prevalence and predictors. Public Health Rep. 111 (Suppl. 2), 40–43 (1996).

In the paper

“However, the search for genetic and epigenetic contributions to obesity-induced hypertension has been disappointing, explaining only a tiny fraction of hypertension31.”

What the sources say

• Not checked yetcites [31] Harrap, S. B. & Charchar, F. J. Genetics of blood pressure: time to curate the collection. J. Hypertens. 35, 1360–1362 (2017). source

In the paper

“VAT reduction following bariatric surgery (for example, vertical sleeve gastrectomy or Roux-en-Y gastric bypass) rapidly decreases BP16,17.”

What the sources say

• Not checked yetcites [16] Schiavon, C. A. et al. Effects of bariatric surgery in obese patients with hypertension: the GATEWAY randomized trial (gastric bypass to treat obese patients with steady hypertension). Circulation 137, 1132–1142 (2018). source
• Not checked yetcites [17] Schauer, P. R. et al. Bariatric surgery versus intensive medical therapy for diabetes — 5-year outcomes. N. Engl. J. Med. 376, 641–651 (2017). source

In the paper

“Substantial evidence indicates that excess visceral adipose tissue (VAT) conveys a higher risk of cardiometabolic disorders, including hypertension and T2DM, than does excess subcutaneous adipose tissue (SAT)”

What the sources say

• Not checked yetcites [13] Neeland, I. J., Poirier, P. & Despres, J. P. Cardiovascular and metabolic heterogeneity of obesity: clinical challenges and implications for management. Circulation 137, 1391–1406 (2018). source
• Not checked yetcites [14] Tchernof, A. & Despres, J. P. Pathophysiology of human visceral obesity: an update. Physiol. Rev. 93, 359–404 (2013). source

In the paper

“the frequency distribution for BP seems to be displaced to higher levels by visceral obesity, increasing the likelihood that BP will be considered hypertensive (FIG. 1).”

In the paper

“In the Nurses’ Health Study and the Health Professionals Follow-up Study, increases in body weight during 10 years of follow-up were associated with higher risk of hypertension, even within a range of BMIs that were considered normal29.”

What the sources say

• Not checked yetcites [29] Field, A. E. et al. Impact of overweight on the risk of developing common chronic diseases during a 10-year period. Arch. Intern. Med. 161, 1581–1586 (2001). source

In the paper

“among obese individuals with similar BMI or total body adiposity, those with greater visceral and ectopic fat generally have higher cardiometabolic risk than those with less VAT13.”

What the sources say

• Not checked yetcites [13] Neeland, I. J., Poirier, P. & Despres, J. P. Cardiovascular and metabolic heterogeneity of obesity: clinical challenges and implications for management. Circulation 137, 1391–1406 (2018). source

In the paper

“These differences can limit the translation of results from rodent models to the understanding of obesity-induced cardiorenal changes in humans.”

In the paper

“many commonly used genetic models of obesity, such as ob/ob and db/db mice and Zucker fatty rats, have derangements of adipokine (for example, leptin) signalling and/or nervous system networks (for example, proopiomelanocortin (POMC)-melanocortin signalling) that mediate sympathetic hyperactivity and hypertension in obesity6.”

What the sources say

• Not checked yetcites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). source

In the paper

“rodents with genetic or diet-induced obesity do not show adherence of fat to the renal capsule and resulting kidney compression as occurs in obese dogs, rabbits and humans6.”

What the sources say

• Not checked yetcites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). source

In the paper

“Excessive weight gain increases heart rate (HR) and cardiac output (CO) in experimental animals and in humans35,36 (TABLE 1).”

What the sources say

• Not checked yetcites [35] Hall, J. E., Crook, E. D., Jones, D. W., Wofford, M. R. & Dubbert, P. M. Mechanisms of obesity-associated cardiovascular and renal disease. Am. J. Med. Sci. 324, 127–137 (2002). source
• Not checked yetcites [36] Alpert, M. A., Karthikeyan, K., Abdullah, O. & Ghadban, R. Obesity and cardiac remodeling in adults: mechanisms and clinical implications. Prog. Cardiovasc. Dis. 61, 114–123 (2018). source

In the paper

“Haemodynamic changes in obesity, including hypertension, increased venous return and increased CO levels, predispose the heart to left ventricular hypertrophy (LVH) with increased wall thickness and chamber size.”

In the paper

“blockade of NO synthesis abrogated glomerular hyperfiltration in dogs with aldosterone-induced hypertension50.”

What the sources say

• Not checked yetcites [50] Granger, J. P. et al. Role of nitric oxide in modulating renal function and arterial pressure during chronic aldosterone excess. Am. J. Physiol. 276, R197–R202 (1999).

In the paper

“Excessive sodium reabsorption by the kidneys initiates the sodium retention, increased extracellular fluid volume and elevated BP that are associated with excess weight gain.”

In the paper

“Obesity-induced glomerular hyperfiltration is associated with vasodilation of renal afferent arterioles and increased glomerular hydrostatic pressure, similar to that observed in diabetes mellitus and hyperglycaemia35,42.”

What the sources say

• Not checked yetcites [35] Hall, J. E., Crook, E. D., Jones, D. W., Wofford, M. R. & Dubbert, P. M. Mechanisms of obesity-associated cardiovascular and renal disease. Am. J. Med. Sci. 324, 127–137 (2002). source
• Not checked yetcites [42] Tonneijck, L. et al. Glomerular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment. J. Am. Soc. Nephrol. 28, 1023–1039 (2017). source

In the paper

“individuals who gain excess adiposity maintain sodium balance at higher BPs than when they were lean, indicating impaired renal-pressure natriuresis16,51.”

What the sources say

• Not checked yetcites [16] Schiavon, C. A. et al. Effects of bariatric surgery in obese patients with hypertension: the GATEWAY randomized trial (gastric bypass to treat obese patients with steady hypertension). Circulation 137, 1132–1142 (2018). source
• Not checked yetcites [51] Hall, J. E. Renal dysfunction, rather than nonrenal vascular dysfunction, mediates salt-induced hypertension. Circulation 133, 894–906 (2016). source

In the paper

“Increased RBF also contributes to increases in venous return and CO in individuals with obesity6.”

What the sources say

• Not checked yetcites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). source

In the paper

“Thus, crosssectional studies may not reveal time-dependent cardiorenal changes that initiate the development of obesity-induced hypertension.”

In the paper

“Pressure in the abdominal cavity may be elevated to >40 cm H20 in patients with large sagittal abdominal diameters52.”

What the sources say

• Not checked yetcites [52] Sugerman, H., Windsor, A., Bessos, M. & Wolfe, L. Intra-abdominal pressure, sagittal abdominal diameter and obesity comorbidity. J. Intern. Med. 241, 71–79 (1997). source

In the paper

“In obesity, chronic elevations in resting HR are caused mainly by reduced parasympathetic tone rather than by increases in sympathetic activity or intrinsic HR6,37.”

What the sources say

• Not checked yetcites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). source
• Not checked yetcites [37] Van Vliet, B. N., Hall, J. E., Mizelle, H. L., Montani, J. P. & Smith, M. J. Jr. Reduced parasympathetic control of heart rate in obese dogs. Am. J. Physiol. 269, H629–H637 (1995).

In the paper

“Thus, obesity is associated with eccentric and concentric LVH36,41.”

What the sources say

• Not checked yetcites [36] Alpert, M. A., Karthikeyan, K., Abdullah, O. & Ghadban, R. Obesity and cardiac remodeling in adults: mechanisms and clinical implications. Prog. Cardiovasc. Dis. 61, 114–123 (2018). source
• Not checked yetcites [41] Lavie, C. J., Arena, R., Alpert, M. A., Milani, R. V. & Ventura, H. O. Management of cardiovascular diseases in patients with obesity. Nat. Rev. Cardiol. 15, 45–56 (2018). source

In the paper

“For reasons that are still unclear, obesity enhances BP sensitivity to AngII62.”

What the sources say

• Not checked yetcites [62] Alonso-Galicia, M., Brands, M. W., Zappe, D. H. & Hall, J. E. Hypertension in obese Zucker rats. Role of angiotensin II and adrenergic activity. Hypertension 28, 1047–1054 (1996). source

In the paper

“In dogs fed an HFD to produce obesity, MR antagonism with eplerenone blunted sodium retention, glomerular hyperfiltration and the development of hypertension by >50%47.”

What the sources say

• Not checked yetcites [47] de Paula, R. B., da Silva, A. A. & Hall, J. E. Aldosterone antagonism attenuates obesity-induced hypertension and glomerular hyperfiltration. Hypertension 43, 41–47 (2004). source

In the paper

“As mentioned above, blockade of the RAAS with AngII receptor blockers, angiotensin-converting enzyme (ACE) inhibitors or renin inhibitors reduces BP in patients with obesity and hypertension64–66.”

What the sources say

• Not checked yetcites [64] Dorresteijn, J. A. et al. Differential effects of renin-angiotensin-aldosterone system inhibition, sympathoinhibition and diuretic therapy on endothelial function and blood pressure in obesity-related hypertension: a double-blind, placebo-controlled cross-over trial. J. Hypertens. 31, 393–403 (2013). source
• Not checked yetcites [65] Grassi, G. et al. Comparative effects of candesartan and hydrochlorothiazide on blood pressure, insulin sensitivity, and sympathetic drive in obese hypertensive individuals: results of the CROSS study. J. Hypertens. 21, 1761–1769 (2003). source
• Not checked yetcites [66] Reisin, E. et al. Lisinopril versus hydrochlorothiazide in obese hypertensive patients: a multicenter placebo-controlled trial. Treatment in Obese Patients With Hypertension (TROPHY) study group. Hypertension 30, 140–145 (1997). source

In the paper

“Antagonism of the RAAS with ACE inhibitors or AngII receptor blockers also attenuates, but may not completely halt, the progression of kidney injury in patients with obesity, hypertension and T2DM67,68.”

What the sources say

• Not checked yetcites [67] Brenner, B. M. et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl. J. Med. 345, 861–869 (2001). source
• Not checked yetcites [68] Lewis, E. J. et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N. Engl. J. Med. 345, 851–860 (2001). source

In the paper

“A randomized controlled trial in patients with primary hypertension showed that treatment with the aldosterone synthase inhibitor LCI699 reduced serum aldosterone levels and BP79.”

What the sources say

• Not checked yetcites [79] Calhoun, D. A. et al. Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placebo- and active-controlled phase 2 trial. Circulation 124, 1945–1955 (2011). source

In the paper

“Stimulation of the RAAS in obesity occurs despite sodium retention and increased BP, which normally inhibit renin secretion, AngII formation and aldosterone secretion.”

In the paper

“In patients with obesity and hypertension, MR antagonism with spironolactone reduced BP and urinary albumin excretion even after long-term blockade of AngII formation with ACE inhibitors72.”

What the sources say

• Not checked yetcites [72] Bomback, A. S., Muskala, P., Bald, E., Chwatko, G. & Nowicki, M. Low-dose spironolactone, added to long-term ACE inhibitor therapy, reduces blood pressure and urinary albumin excretion in obese patients with hypertensive target organ damage. Clin. Nephrol. 72, 449–456 (2009). source

In the paper

“Experimental animals and people with obesity generally have modest increases in most components of the RAAS, including angiotensin II (AngII) and aldosterone6,59.”

What the sources say

• Not checked yetcites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). source
• Not checked yetcites [59] Engeli, S. & Sharma, A. M. The renin-angiotensin system and natriuretic peptides in obesity-associated hypertension. J. Mol. Med. 79, 21–29 (2001). source

In the paper

“In 2,923 participants from the Framingham Heart Study, high RSF levels (fatty kidney) conveyed a 2.2-fold increased risk of hypertension20.”

What the sources say

• Not checked yetcites [20] Foster, M. C. et al. Fatty kidney, hypertension, and chronic kidney disease: the Framingham Heart Study. Hypertension 58, 784–790 (2011). source

In the paper

“Current evidence suggests that mild elevations in AngII levels in obesity are driven largely by increased renal renin secretion due to SNS activation, kidney compression and perhaps other factors such as adipokines51,60.”

What the sources say

• Not checked yetcites [51] Hall, J. E. Renal dysfunction, rather than nonrenal vascular dysfunction, mediates salt-induced hypertension. Circulation 133, 894–906 (2016). source
• Not checked yetcites [60] Cabandugama, P. K., Gardner, M. J. & Sowers, J. R. The renin angiotensin aldosterone system in obesity and hypertension: roles in the cardiorenal metabolic syndrome. Med. Clin. North Am. 101, 129–137 (2017). source

In the paper

“High levels of RSF were also associated with a 2.3-fold increased risk of CKD after adjusting for VAT and BMI20.”

What the sources say

• Not checked yetcites [20] Foster, M. C. et al. Fatty kidney, hypertension, and chronic kidney disease: the Framingham Heart Study. Hypertension 58, 784–790 (2011). source

In the paper

“Increases in total tissue pressure and interstitial fluid hydrostatic pressure to −19 mmHg have been observed in obese dogs56.”

What the sources say

• Not checked yetcites [56] Hall, J. E., Brands, M. W. & Henegar, J. R. Mechanisms of hypertension and kidney disease in obesity. Ann. NY Acad. Sci. 892, 91–107 (1999). source

In the paper

“Preclinical studies in mice suggest that aldosterone synthase inhibition may amplify diet-induced hyperinsulinaemia and obesity81; such adverse effects have not been reported for MR antagonists.”

What the sources say

• Not checked yetcites [81] Liao, W. H. et al. Aldosterone deficiency in mice burdens respiration and accentuates diet-induced hyperinsulinemia and obesity. JCI Insight 3, 99015 (2018). source

In the paper

“Moreover, in patients with obesity and treatment-resistant hypertension who were treated with spironolactone, the resulting reductions in BP did not correlate with plasma aldosterone concentration73,74.”

What the sources say

• Not checked yetcites [73] Dudenbostel, T. & Calhoun, D. A. Use of aldosterone antagonists for treatment of uncontrolled resistant hypertension. Am. J. Hypertens. 30, 103–109 (2017). source
• Not checked yetcites [74] de Souza, F., Muxfeldt, E., Fiszman, R. & Salles, G. Efficacy of spironolactone therapy in patients with true resistant hypertension. Hypertension 55, 147–152 (2010). source

In the paper

“In the Dallas Heart Study, increased VAT, but not total or subcutaneous adiposity, was strongly associated with incident hypertension during a median follow-up of 7 years21.”

What the sources say

• Not checked yetcites [21] Chandra, A. et al. The relationship of body mass and fat distribution with incident hypertension: observations from the dallas heart study. J. Am. Coll. Cardiol. 64, 997–1002 (2014). source

In the paper

“In obese rabbits, dogs and humans, the levels of renal medullary glycosaminoglycans, especially hyaluronan, which is an important component of the ECM and is often associated with tissue inflammation and oedema, were markedly elevated compared with lean controls53–55.”

What the sources say

• Not checked yetcites [53] Hall, J. E. Louis, K. Dahl Memorial Lecture. Renal and cardiovascular mechanisms of hypertension in obesity. Hypertension 23, 381–394 (1994). source
• Not checked yetcites [54] Alonso-Galicia, M., Dwyer, T. M., Herrera, G. A. & Hall, J. E. Increased hyaluronic acid in the inner renal medulla of obese dogs. Hypertension 25, 888–892 (1995). source
• Not checked yetcites [55] Dwyer, T. M. et al. Distribution of renal medullary hyaluronan in lean and obese rabbits. Kidney Int. 58, 721–729 (2000). source

In the paper

“increases in PRF and RSF increased the risk of hypertension independent of BMI and VAT.”

In the paper

“Although obesity causes only modest increases in AngII formation, pharmacological RAAS blockade blunts sodium retention and hypertension in obesity6.”

What the sources say

• Not checked yetcites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). source

In the paper

“Aldosterone synthase inhibitors have been shown to attenuate cardiac and renal injury in models of experimental hypertension, such as spontaneously hypertensive rats (SHRs) and uninephrectomized rats fed a high-salt diet77,78, but their efficacy in obesity-induced hypertension is unclear.”

What the sources say

• Not checked yetcites [77] Andersen, K. Aldosterone synthase inhibition in hypertension. Curr. Hypertens. Rep. 15, 484–488 (2013). source
• Not checked yetcites [78] Namsolleck, P. & Unger, T. Aldosterone synthase inhibitors in cardiovascular and renal diseases. Nephrol. Dial. Transplant. 29, i62–i68 (2014). source

In the paper

“In addition, Racl inhibitors amelio-rated proteinuria and kidney injury in obese rodents and in rodents with salt-sensitive hypertension82.”

What the sources say

• Not checked yetcites [82] Fujita, T. Mechanism of salt-sensitive hypertension: focus on adrenal and sympathetic nervous systems. J. Am. Soc. Nephrol. 25, 1148–1155 (2014). source

In the paper

“These studies indicate that MR antagonism is an important therapy for obesity-induced hypertension and its associated cardiorenal abnormalities even in the absence of hyperaldosteronism.”

In the paper

“In addition, genetically engineered mice with increased circulating levels of ANP and BNP (owing to a lack of receptors that promote clearance of these NPs) showed ‘beiging of white adipocytes and increased thermogenesis compared with wild-type mice99.”

What the sources say

• Not checked yetcites [99] Bordicchia, M. et al. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J. Clin. Invest. 122, 1022–1036 (2012). source

In the paper

“These findings suggest that an altered GM may be, in part, secondary to increased BP or activation of the RAAS and SNS, which are known to contribute to hypertension in SHRs.”

In the paper

“The pathogenic role of VAT, beyond its contributions to overall adiposity, may be related to secretion of cytokines such as tumour necrosis factor (TNF) and IL-6 14 that contribute to inflammation, insulin resistance and increased BP.”

What the sources say

• Not checked yetcites [14] Tchernof, A. & Despres, J. P. Pathophysiology of human visceral obesity: an update. Physiol. Rev. 93, 359–404 (2013). source

In the paper

“In SHRs, BP reduction as a result of ACE inhibition had beneficial effects on gut pathology (for example, reductions in mucosal permeability, inflammation and dysbiosis)105.”

What the sources say

• Not checked yetcites [105] Santisteban, M. M. et al. Hypertension-linked pathophysiological alterations in the gut. Circ. Res. 120, 312–323 (2017). source

In the paper

“Consistent with this hypothesis, transgenic mice that overexpressed BNP were protected against diet-induced obesity and insulin resistance98.”

What the sources say

• Not checked yetcites [98] Miyashita, K. et al. Natriuretic peptides/cGMP/cGMP-dependent protein kinase cascades promote muscle mitochondrial biogenesis and prevent obesity. Diabetes 58, 2880–2892 (2009). source

In the paper

“Although production of SCFAs provides a plausible link between the GM and BP regulation, limited direct evidence exists for a cause-and-effect relationship in obesity-induced hypertension.”

In the paper

“Men with obesity and hypertension had lower plasma pro ANP levels than normotensive lean men despite greater sodium intake and larger left atria90,91.”

What the sources say

• Not checked yetcites [90] Asferg, C. L. et al. Relative atrial natriuretic peptide deficiency and inadequate renin and angiotensin II suppression in obese hypertensive men. Hypertension 62, 147–153 (2013). source
• Not checked yetcites [91] Asferg, C. L., Andersen, U. B., Linneberg, A., Goetze, J. P. & Jeppesen, J. L. Obese hypertensive men have lower circulating proatrial natriuretic peptide concentrations despite greater left atrial size. Am. J. Hypertens. 31, 645–650 (2018). source

In the paper

“Increases in NPs associated with high salt intake and volume loading are also diminished in obese compared with lean individuals90–92.”

What the sources say

• Not checked yetcites [90] Asferg, C. L. et al. Relative atrial natriuretic peptide deficiency and inadequate renin and angiotensin II suppression in obese hypertensive men. Hypertension 62, 147–153 (2013). source
• Not checked yetcites [91] Asferg, C. L., Andersen, U. B., Linneberg, A., Goetze, J. P. & Jeppesen, J. L. Obese hypertensive men have lower circulating proatrial natriuretic peptide concentrations despite greater left atrial size. Am. J. Hypertens. 31, 645–650 (2018). source
• Not checked yetcites [92] Savoia, C., Volpe, M., Alonzo, A., Rossi, C. & Rubattu, S. Natriuretic peptides and cardiovascular damage in the metabolic syndrome: molecular mechanisms and clinical implications. Clin. Sci. 118, 231–240 (2010). source

In the paper

“Increased VAT and SAT volume as well as reduced adipose tissue quality (assessed indirectly as reduced attenuation in Hounsfield units on CT) were reported to be associated with increased cardiovascular risk that was not explained by increased BMI111.”

What the sources say

• Not checked yetcites [111] Abraham, T. M., Pedley, A., Massaro, J. M., Hoffmann, U. & Fox, C. S. Association between visceral and subcutaneous adipose depots and incident cardiovascular disease risk factors. Circulation 132, 1639–1647 (2015). source

In the paper

“MR can also be activated by glucocorticoids in the setting of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) deficiency83.”

What the sources say

• Not checked yetcites [83] Chapman, K., Holmes, M. & Seckl, J. 11beta-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Physiol. Rev. 93, 1139–1206 (2013). source

In the paper

“The GLP1 agonist liraglutide and dipeptidyl peptidase 4 (DPP4) inhibitors, which attenuate degradation of GLP1, lower BP in obese animals and in patients with hypertension and T2DM108.”

What the sources say

• Not checked yetcites [108] Afsar, B., Vaziri, N. D., Aslan, G., Tarim, K. & Kanbay, M. Gut hormones and gut microbiota: implications for kidney function and hypertension. J. Am. Soc. Hypertens. 10, 954–961 (2016). source

In the paper

“Adipocytes are much more than just energy-storage depots — they secrete many bioactive substances that influence metabolic and cardiovascular functions, including BP110.”

What the sources say

• Not checked yetcites [110] Zhu, Q. & Scherer, P. E. Immunologic and endocrine functions of adipose tissue: implications for kidney disease. Nat. Rev. Nephrol. 14, 105–120 (2018). source

In the paper

“In the Framingham Heart Study, participants with obesity had lower circulating amino-terminal pro-ANP concentrations than those who had normal BMI93.”

What the sources say

• Not checked yetcites [93] Wang, T. J. et al. Impact of obesity on plasma natriuretic peptide levels. Circulation 109, 594–600 (2004). source

In the paper

“In particular, digestion of dietary fibre by the GM produces short-chain fatty acids (SCFAs) including acetate, propionate and butyrate.”

In the paper

“Thus, increased levels of neprilysin and upregulation of NPR-C in obesity could contribute to a relative NP deficiency and impaired NaCl homeostasis despite increased cardiac filling pressures and volume loading.”

In the paper

“The LepR is expressed in multiple regions of the forebrain and hindbrain, including the hypothalamus, brainstem vasomotor centres and intermediolateral nucleus (IML) of the spinal cord119,135,138 (FIG. 5a).”

What the sources say

• Not checked yetcites [119] Pan, W. W. & Myers, M. G. Jr. Leptin and the maintenance of elevated body weight. Nat. Rev. Neurosci. 19, 95–105 (2018). source
• Not checked yetcites [135] Munzberg, H. & Myers, M. G. Jr. Molecular and anatomical determinants of central leptin resistance. Nat. Neurosci. 8, 566–570 (2005). source
• Not checked yetcites [138] Mark, A. L. et al. Leptin signaling in the nucleus tractus solitarii increases sympathetic nerve activity to the kidney. Hypertension 53, 375–380 (2009). source

In the paper

“Leptin infusions in rodents over several days also cause mild, gradual increases in BP and HR125–127.”

What the sources say

• Not checked yetcites [125] Shek, E. W., Brands, M. W. & Hall, J. E. Chronic leptin infusion increases arterial pressure. Hypertension 31, 409–414 (1998). source
• Not checked yetcites [126] Mark, A. L. Selective leptin resistance revisited. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305, R566–R581 (2013). source
• Not checked yetcites [127] Kuo, J. J., Jones, O. B. & Hall, J. E. Inhibition of NO synthesis enhances chronic cardiovascular and renal actions of leptin. Hypertension 37, 670–676 (2001). source

In the paper

“Adiponectin supplementation reduced BP in salt-fed, adiponectin-knockout mice and in KKAy mice, which develop obesity via ectopic expression of agouti protein117.”

What the sources say

• Not checked yetcites [117] Ohashi, K. et al. Adiponectin replenishment ameliorates obesity-related hypertension. Hypertension 47, 1108–1116 (2006). source

In the paper

“Moreover, these leptin-deficient individuals displayed evidence of autonomic dysfunction, including postural hypotension, reduced BP responses to cold pressor stimuli and diminished RAAS responses to upright posture.”

What the sources say

• Not checked yetcites [134] Ozata, M., Ozdemir, I. C. & Licinio, J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J. Clin. Endocrinol. Metab. 84, 3686–3695 (1999). source

In the paper

“These observations, together with the findings in rodents discussed above, are consistent with the concept that leptin may act as a link between obesity, SNA and hypertension.”

In the paper

“Plasma leptin concentration is highly correlated with SNA activity123, and acute leptin infusions increase SNA in the brown adipose tissue, adrenal glands and kidneys of rodents124.”

What the sources say

• Not checked yetcites [123] Snitker, S., Pratley, R. E., Nicolson, M., Tataranni, P. A. & Ravussin, E. Relationship between muscle sympathetic nerve activity and plasma leptin concentration. Obes. Res. 5, 338–340 (1997). source

In the paper

“Similar to findings in rodents, acute leptin administration stimulates SNA in humans132.”

What the sources say

• Not checked yetcites [132] Machleidt, F. et al. Experimental hyperleptinemia acutely increases vasoconstrictory sympathetic nerve activity in healthy humans. J. Clin. Endocrinol. Metab. 98, E491–E496 (2013). source

In the paper

“The chronic hypertensive effects of leptin were greatly potentiated after inhibition of NO synthesis despite weight loss that was associated with decreased food intake127.”

What the sources say

• Not checked yetcites [127] Kuo, J. J., Jones, O. B. & Hall, J. E. Inhibition of NO synthesis enhances chronic cardiovascular and renal actions of leptin. Hypertension 37, 670–676 (2001). source

In the paper

“In contrast to adiponectin, leptin is secreted in increasing amounts as adipocytes enlarge119,120.”

What the sources say

• Not checked yetcites [119] Pan, W. W. & Myers, M. G. Jr. Leptin and the maintenance of elevated body weight. Nat. Rev. Neurosci. 19, 95–105 (2018). source
• Not checked yetcites [120] Schwartz, M. W. et al. Central nervous system control of food intake. Nature 404, 661–671 (2000). source

In the paper

“The anorexic effects of acute leptin injections are attenuated in individuals with obesity135.”

What the sources say

• Not checked yetcites [135] Munzberg, H. & Myers, M. G. Jr. Molecular and anatomical determinants of central leptin resistance. Nat. Neurosci. 8, 566–570 (2005). source

In the paper

“Thus, the SNS effects of leptin may involve multiple neuronal populations.”

In the paper

“Deletion of LepR in the hypothalamic arcuate nucleus (ARC) of mice blocked much of the elevated RSNA that was evoked by leptin139.”

What the sources say

• Not checked yetcites [139] Harlan, S. M. et al. Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation. Circ. Res. 108, 808–812 (2011). source

In the paper

“The observation that LepR antagonism decreased BP and SNA in obese rabbits supports the importance of leptin in obesity hypertension129.”

What the sources say

• Not checked yetcites [129] Lim, K., Burke, S. L. & Head, G. A. Obesity-related hypertension and the role of insulin and leptin in high-fat-fed rabbits. Hypertension 61, 628–634 (2013). source

In the paper

“Selective LepR deletion in POMC neurons of the ARC and brainstem also abolished BP increases in mice during chronic leptin infusions140.”

What the sources say

• Not checked yetcites [140] do Carmo, J. M. et al. Control of blood pressure, appetite, and glucose by leptin in mice lacking leptin receptors in proopiomelanocortin neurons. Hypertension 57, 918–926 (2011). source

In the paper

“A study that included four patients with leptin deficiency due to gene mutations found that despite severe obesity, three of these patients had normal BP and only one had high BP, possibly owing to unexplained high levels of adrenocorticotropic hormone, which can increase plasma cortisol levels as well as BP134.”

What the sources say

• Not checked yetcites [134] Ozata, M., Ozdemir, I. C. & Licinio, J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J. Clin. Endocrinol. Metab. 84, 3686–3695 (1999). source

In the paper

“Although the effect of chronic leptin infusion on SNA in humans has not yet been reported, administration of recombinant leptin for 12 weeks failed to increase BP in overweight or obese adults133.”

What the sources say

• Not checked yetcites [133] Zelissen, P. M. et al. Effect of three treatment schedules of recombinant methionyl human leptin on body weight in obese adults: a randomized, placebo-controlled trial. Diabetes Obes. Metab. 7, 755–761 (2005). source

In the paper

“RSNA, assessed by kidney noradrenaline spillover, is also higher in individuals with obesity than in those who are non-obese and normotensive152,154.”

What the sources say

• Not checked yetcites [152] Grassi, G., Mark, A. & Esler, M. The sympathetic nervous system alterations in human hypertension. Circ. Res. 116, 976–990 (2015). source
• Not checked yetcites [154] Esler, M. et al. Obesity paradox in hypertension: is this because sympathetic activation in obesity-hypertension takes a benign form? Hypertension 71, 22–33 (2018). source

In the paper

“However, sympathetic blockade in patients with obesity or in experimental animals with dietary-induced obesity consistently reduces BP6,158.”

What the sources say

• Not checked yetcites [6] Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015). source
• Not checked yetcites [158] Wofford, M. R. et al. Antihypertensive effect of alpha- and beta-adrenergic blockade in obese and lean hypertensive subjects. Am. J. Hypertens. 14, 694–698 (2001). source

In the paper

“In contrast to skeletal muscle and kidneys, heart SNA may be within the normal range, or perhaps even reduced, in patients with obesity and hypertension152”

What the sources say

• Not checked yetcites [152] Grassi, G., Mark, A. & Esler, M. The sympathetic nervous system alterations in human hypertension. Circ. Res. 116, 976–990 (2015). source

In the paper

“Part of this variability may relate to differences in VAT, which seems to be more closely correlated with increased SNA and hypertension than does overall adiposity156.”

What the sources say

• Not checked yetcites [156] Davy, K. P. & Hall, J. E. Obesity and hypertension: two epidemics or one? Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R803–R813 (2004). source

In the paper

“In summary, obesity elicits complex alterations in renal, SNS, endothelial and vascular function that may augment the effects of leptin on SNA and BP.”

In the paper

“In rabbits, RSNA increases within a few days of starting an HFD155.”

What the sources say

• Not checked yetcites [155] Armitage, J. A. et al. Rapid onset of renal sympathetic nerve activation in rabbits fed a high-fat diet. Hypertension 60, 163–171 (2012). source

In the paper

“The renal nerves may mediate most of the BP effects of sympathetic activation in obesity.”

In the paper

“Increased RSNA in individuals with obesity contributes to increases in renin secretion, sodium reabsorption and BP159–161.”

What the sources say

• Not checked yetcites [159] Kassab, S. et al. Endothelin-A receptor antagonism attenuates the hypertension and renal injury in Dahl salt-sensitive rats. Hypertension 31, 397–402 (1998). source
• Not checked yetcites [160] Lohmeier, T. E. et al. Systemic and renal-specific sympathoinhibition in obesity hypertension. Hypertension 59, 331–338 (2012). source
• Not checked yetcites [161] Henegar, J. R. et al. Catheter-based radiorefrequency renal denervation lowers blood pressure in obese hypertensive dogs. Am. J. Hypertens. 27, 1285–1292 (2014). source

In the paper

“In humans, skeletal MSNA, measured by microneurography, increases even with modest weight gain153.”

What the sources say

• Not checked yetcites [153] Gentile, C. L., Orr, J. S., Davy, B. M. & Davy, K. P. Modest weight gain is associated with sympathetic neural activation in nonobese humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R1834–R1838 (2007). source

In the paper

“These findings indicate that increased sympathetic activity is an important contributor to the development and maintenance of obesity-induced hypertension.”

In the paper

“The role of the SNS in linking obesity with elevated BP has been well documented in experimental models and in humans121,152.”

What the sources say

• Not checked yetcites [121] Hall, J. E. et al. Obesity-induced hypertension: role of sympathetic nervous system, leptin, and melanocortins. J. Biol. Chem. 285, 17271–17276 (2010). source
• Not checked yetcites [152] Grassi, G., Mark, A. & Esler, M. The sympathetic nervous system alterations in human hypertension. Circ. Res. 116, 976–990 (2015). source

In the paper

“The acute stimulatory effect of leptin on RSNA in anaesthetized mice was nearly abolished by pharmacological inhibition of PI3K143.”

What the sources say

• Not checked yetcites [143] Rahmouni, K., Haynes, W. G., Morgan, D. A. & Mark, A. L. Intracellular mechanisms involved in leptin regulation of sympathetic outflow. Hypertension 41, 763–767 (2003). source

In the paper

“The IRS2-PI3K pathway also contributes to the effects of leptin on SNA and BP.”

What the sources say

• Not checked yetcites [143] Rahmouni, K., Haynes, W. G., Morgan, D. A. & Mark, A. L. Intracellular mechanisms involved in leptin regulation of sympathetic outflow. Hypertension 41, 763–767 (2003). source
• Not checked yetcites [144] do Carmo, J. M., da Silva, A. A. & Hall, J. E. Leptin reduces food intake but fails to raise blood pressure in mice with deficiency of insulin receptor substrate 2 (IRS2) in the entire brain or specifically in POMC neurons. Hypertension 60, A27 (2012). source