Modulation of pressure-natriuresis by renal medullary reactive oxygen species and nitric oxide
Open accessAbstract
The renal pressure-natriuresis mechanism is the dominant controller of body fluid balance and long-term arterial pressure. In recent years, it has become clear that the balance of reactive oxygen and nitrogen species within the renal medullary region is a key determinant of the set point of the renal pressure-natriuresis curve. The development of renal medullary oxidative stress causes dysfunction of the pressure-natriuresis mechanism and contributes to the development of hypertension in numerous disease models. The purpose of this review is to point out the known mechanisms within the renal medulla through which reactive oxygen and nitrogen species modulate the pressure-natriuresis response and to update the reader on recent advances in this field.
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The existence of the pressure-natriuresis mechanism is well established but remains surprisingly poorly understood.
“The existence of this pressure‐natriuresis mechanism is well established,1 but remains surprisingly poorly understood.26, 27”
From A Quantitative Systems Physiology Model of Renal Function and Blood Pressure Regulation: Model Description (2017) · cites this paper as [27]
In “The Renal Medulla and Pressure-Natriuresis,” the review says certain aspects of the mechanism remain unclear and controversial. It also says the mechanisms have become increasingly clear over several decades, so it does not support the broader characterization that pressure-natriuresis remains poorly understood. (LLM, conf=0.86)
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Cites
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Ortiz, P. A., Hong, N. J., & Garvin, J. L. (2001) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.2001.281.5.f819 · Cited by 159 · see citing works
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Li, N., Yi, F.-X., Spurrier, J. L., Bobrowitz, C. A., & Zou, A.-P. (2002) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00218.2001 · Cited by 131 · cited 1× · see citing works
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Juncos, R., & Garvin, J. L. (2005) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00348.2004 · Cited by 112 · cited 1× · see citing works
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“[19] first demonstrated that NO blockade blunted increases in renal medullary blood flow and sodium excretion in response to acute increases in renal arterial pressure.”
BackgroundMECHANISMS MEDIATING PRESSURE NATRIURESIS: WHAT WE KNOW and WHAT WE NEED TO FIND OUT
Evans, R. G., Majid, D. S. A., & Eppel, G. A. (2005) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2005.04202.x · Cited by 98 · cited 2× · see citing works
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BackgroundMethodINTRARENAL OXYGEN AND HYPERTENSION
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Effect of renal medullary H2O2 on salt-induced hypertension and renal injury
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“A number of studies in our laboratory have demonstrated that the net effect of H2O2 within the renal medulla is to reduce medullary perfusion and sodium excretion [29, 30].”
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BackgroundNitric Oxide–Induced Inhibition of Transport by Thick Ascending Limbs From Dahl Salt-Sensitive Rats
Garcia, N. H., Plato, C. F., Stoos, B. A., & Garvin, J. L. (1999) · Hypertension · doi:10.1161/01.hyp.34.3.508 · Cited by 80 · cited 1× · see citing works
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BackgroundRenal medullary ETBreceptors produce diuresis and natriuresis via NOS1
Nakano, D., Pollock, J. S., & Pollock, D. M. (2008) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00578.2007 · Cited by 79 · cited 1× · see citing works
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Szentiványi, M., Zou, A.-P., Mattson, D. L., Soares, P., Moreno, C., Roman, R. J., & Cowley, A. W. (2002) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00461.2001 · Cited by 78 · cited 2× · see citing works
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BackgroundLi, N., Chen, L., Yi, F., Xia, M., & Li, P. (2008) · Circulation Research · doi:10.1161/circresaha.107.169201 · Cited by 68 · cited 1× · see citing works
“ascending limb [33••], and the demonstration of the importance of HIF-1α signaling in preventing saltsensitive hypertension [ 50 ].”
BackgroundRegulation of thick ascending limb transport: role of nitric oxide
Herrera, M., Ortiz, P. A., & Garvin, J. L. (2006) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00465.2005 · Cited by 66 · cited 1× · see citing works
“NO, in addition to reducing tubular sodium transport [45] and increasing medullary blood flow [12], has direct effects on the mitochondria to limit respiration and O2 use, thereby acting to increase local pO2 [46].”
BackgroundOxygen availability limits renal NADPH-dependent superoxide production
Chen, Y., Gill, P. S., & Welch, W. J. (2005) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00115.2005 · Cited by 62 · cited 1× · see citing works
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BackgroundArginine Vasopressin–Mediated Stimulation of Nitric Oxide Within the Rat Renal Medulla
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“[20••], but O2 , which can be converted to H2O2 by the action of the enzyme superoxide dismutase (SOD), is known to be produced by the medullary thick ascending limb in response to increased tubular flow and sodium pump activity [27, 28].”
BackgroundNITRIC OXIDE IN THE MEDIATION OF PRESSURE NATRIURESIS
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“exchangers in medullary thick ascending limb [35, 36].”
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Local Renal Medullary L-NAME Infusion Enhances the Effect of Long-Term Angiotensin II Treatment
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“The physiological mechanisms through which renal medullary NO protects from the development of hypertension are likely to vary, but it is known that inhibition of NO production increases the susceptibility of the renal medullary circulation to vasoconstrictor agents such as angiotensin II and vasopressin [15–17].”
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Pressure natriuresis following acute and chronic inhibition of nitric oxide synthase in rats
Guarasci, G., & Kline, R. L. (1996) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1996.270.2.r469 · Cited by 42 · cited 1× · see citing works
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“In situations of reduced medullary NO, administering vasoconstrictor agents in doses that normally are subpressor and do not affect medullary perfusion does result in reduced medullary perfusion and sustained hypertension [14, 18].”
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“Previous studies from our laboratory have demonstrated that inner medullary collecting duct production of NO buffers arginine vasopressin-mediated renal medullary vasoconstriction and prevents hypertension in animals in which circulating vasopressin levels are high [15, 17].”
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Zhang, Z., & Pallone, T. L. (2004) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00394.2003 · Cited by 32 · cited 1× · see citing works
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“However, previous studies suggest that PKG may inhibit NADPH oxidase, the major source of O2 − in medullary thick ascending limb, by preventing translocation of the p47 subunit and activation of the enzyme [34].”
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Riazi, S., Tiwari, S., Sharma, N., Rash, A., & ECELBARGER, C. A. (2009) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.90484.2008 · Cited by 24 · cited 1× · see citing works
“Both renal medullary oxidative stress [37] and increased tubular transport activity of the medullary thick ascending limb have been associated with a number of models of hypertensive disease, including the Dahl salt-sensitive rat [38], and more recently, high-fat–fed Fischer 344 X Brown Norway rats and rats made hyper…”
BackgroundO'Connor, P. M., Lü, L., Schreck, C., & Cowley, A. W. (2008) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00137.2008 · Cited by 20 · see citing works
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“in the renal outer medulla of Dahl salt-sensitive rats [ 43 ], identification of NO-induced cGMP/PKG as a signaling pathway to reduce O 2 � formation in medullary thick”
BackgroundGenetic models of hypertension
Kurtz, T. W. (1994) · The Lancet · doi:10.1016/s0140-6736(94)92761-8 · Cited by 17 · cited 1× · see citing works
“Of particular interest to our own group has been the Dahl salt-sensitive model of hypertension, a genetic rat model that displays many of the traits associated with hypertension in African Americans, such as low renin saltsensitivity and progressive renal disease [40].”
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Renal Autoregulation in Health and Disease
Carlström, M., Wilcox, C. S., & Arendshorst, W. J. (2015) · Physiological Reviews · doi:10.1152/physrev.00042.2012 · Cited by 485 · see citing works
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“In addition, NO and superoxide are important modulators of pressure-natriuresis [165].”
Oxidative Stress in Hypertension: Role of the Kidney
Araújo, M., & Wilcox, C. S. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5259 · Cited by 187 · see citing works
Pressure natriuresis and the renal control of arterial blood pressure
Ivy, J. R., & Bailey, M. A. (2014) · The Journal of Physiology · doi:10.1113/jphysiol.2014.271676 · Cited by 177 · see citing works
Pons, H., Ferrebuz, A., Quiroz, Y., Romero-Vásquez, F., Parra, G., Johnson, R. J., & Rodríguez‐Iturbe, B. (2012) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00517.2012 · Cited by 105 · see citing works
“Renal inflammation is inevitably accompanied by intrarenal oxidative stress and increased local angiotensin II activity (5, 34, 36) that induce renal vasoconstriction, reduce the peritubular capillary network and impair pressure natriuresis (8, 14, 22).”
BackgroundHallow, K. M., Gebremichael, Y., Helmlinger, G., & Vallon, V. (2017) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00497.2016 · Cited by 98 · see citing works
“Na transport in the DCT and CNT/CD is regulated by atrial natriuretic peptide (31), angiotensin II, and aldosterone (35) and may also be affected by renal sympathetic nerve activity and nitric oxide (15, 33, 36).”
BackgroundInfluentialCowley, A. W., Abe, M., Mori, T., O'Connor, P. M., Ohsaki, Y., & Zheleznova, N. N. (2014) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00455.2014 · Cited by 97 · see citing works
“In brief, a number of studies have shown that both O2 and NO (32, 33, 132, 133, 140) and perhaps ATP (141) produced in the mTAL can signal the pericyte cell bodies to constrict or dilate, responses which would modify renal MBF.”
BackgroundMechanisms of sodium balance: total body sodium, surrogate variables, and renal sodium excretion
Bie, P. (2018) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00363.2017 · Cited by 90 · see citing works
Renal Collecting Duct NOS1 Maintains Fluid–Electrolyte Homeostasis and Blood Pressure
Hyndman, K. A., Boesen, E. I., Elmarakby, A. A., Brands, M. W., Huang, P. L., Kohan, D. E., Pollock, D. M., & Pollock, J. S. (2013) · Hypertension · doi:10.1161/hypertensionaha.113.01291 · Cited by 84 · see citing works
“sodium and water reabsorption, independent of PGE, although we cannot rule out that CD NOS1–derived NO regulates vasa recta resistance and medullary blood flow.(40,48)”
BackgroundFranco, M., Tapia, E., Bautista, R., Pacheco, U., Santamaría, J., Quiroz, Y., Johnson, R. J., & Rodríguez‐Iturbe, B. (2013) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00463.2012 · Cited by 80 · see citing works
Involvement of ENaC in the development of salt-sensitive hypertension
Pavlov, T. S., & Staruschenko, A. (2016) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00427.2016 · Cited by 80 · see citing works
“Increased levels of oxidative stress have been many times reported in Dahl SS rats (14, 34, 56) and hypertensive patients (44, 66); this appears to be an attractive signaling mechanism linking a high-salt diet and elevated ENaC activity.”
BackgroundRole of medullary blood flow in the pathogenesis of renal ischemia–reperfusion injury
Regner, K. R., & Roman, R. J. (2011) · Current Opinion in Nephrology & Hypertension · doi:10.1097/mnh.0b013e32834d085a · Cited by 69 · see citing works
Sensing of tubular flow and renal electrolyte transport
Verschuren, E. H. J., Castenmiller, C., Peters, D. J. M., Arjona, F. J., Bindels, R. J. M., & Hoenderop, J. G. J. (2020) · Nature Reviews Nephrology · doi:10.1038/s41581-020-0259-8 · Cited by 67 · see citing works
Inhibition of the purinergic P2X7 receptor improves renal perfusion in angiotensin-II-infused rats
Menzies, R. I., Howarth, A. R., Unwin, R. J., Tam, F. W. K., Mullins, J. J., & Bailey, M. A. (2015) · Kidney International · doi:10.1038/ki.2015.182 · Cited by 64 · see citing works
NAD(P)H oxidase and renal epithelial ion transport
Schreck, C., & O'Connor, P. M. (2011) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00618.2010 · Cited by 62 · see citing works
Renal P2 receptors and hypertension
Menzies, R. I., Unwin, R. J., & Bailey, M. A. (2014) · Acta Physiologica · doi:10.1111/apha.12412 · Cited by 55 · see citing works
“Flow here is influenced by the vasa recta endothelium and by the contractile pericyte with which it is in contact (Pallone et al. 2012).”
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NOX4‐dependent regulation of ENaC in hypertension and diabetic kidney disease
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“Elevated serum urea and levels indicate the signs of renal damage (40).”
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Calcium oxalate nephrolithiasis and expression of matrix GLA protein in the kidneys
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“For example, NO (10, 35) and superoxide (33) produced by the medullary thick ascending limb (mTAL) modulates descending vasa recta tone, thereby regulating medullary blood flow.”
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“In recent years, it has become clear that a key determinant of the set point of the renal pressure-natriuresis curve is the balance of reactive oxygen and nitrogen species within the renal medullary region [11].”
BackgroundResurrecting Hope for Antioxidant Treatment of Cardiovascular Disease
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“However, the PN response is integrated so that paracrine factors, such as nitric oxide (NO; O’Connor & Cowley, 2010) and ATP (Menzies et al. 2015), suppress compensatory reabsorption in the distal nephron.”
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“Other substances including NO (9), renal prostaglandins (7), renal kinins (32), and reactive oxygen species (24) have been proposed to contribute to the mechanism of increased diuresis and natriuresis in response to increased renal perfusion pressure (13).”
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“The renal medulla of SS rats has been shown to have high levels of superoxide anion and hydrogen peroxide activity (26) which contribute to increase in blood pressure in these animals.”
BackgroundPhysiology and Pathophysiology of Hypertension
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“A growing body of evidence supports the hypothesis that the balance between the production of ROS and nitric oxide in the mTAL plays a central role in regulating medullary blood flow, sodium homeostasis, and long-term control of BP [69,70].”
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Intrarenal signaling mediated by CCK plays a role in salt intake-induced natriuresis
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“The thick ascending limbs are additionally known to release key modulators of natriuresis, including ATP (3), 20-hydroxyeicosatetraenoic acid, reactive oxygen species (33), and endothelin-1 (14), during fluid volume expansion.”
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“It is known that oxidative stress with the production of reactive oxygen species (ROS) results in a decrease in the bloodflow in the renal medulla, while the synthesis of nitrogen oxide (NO) promotes the restoration of water and salt homeostasis [36, 37].”
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“52 These findings align with clinical data indicating that there is an increased risk of hypertension in these patients 20,21 and suggest that there may be a long-term pressure natriuresis defect due to abnormal renal medullary structure and function in both humans and mice after reversal of…”
Cerebral Salt Wasting Syndrome in Amyotrophic Lateral Sclerosis: A Rare Occurrence
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“5,6 In our case, carbon dioxide narcosis could possibly be one of the contributing factors.”
- Authors
- O’Connor, P. M., & Cowley, A. W.
- Affiliations
- Medical College of Wisconsin (US)
- ORCID
- Cowley, Allen W.
- Venue
- Current Hypertension Reports
- Published
- 2010-04
- Volume
- 12
- Issue
- 2
- Pages
- 86-92
- ISSN
- 1522-6417 (ISSN-L)
- 1534-3111
- PMC
- PMC3722865
- OpenAlex
- W1965843452
- Cited by
- 62
- References
- 50
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 5 · 2019: 1 · 2018: 3 · 2017: 7 · 2016: 6 · 2015: 5 · 2014: 6 · 2013: 6 · 2012: 5
- FWCI
- 0.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Current Hypertension Reports (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL029587, P01HL082798)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Keywords
- pressure natriuresis, renal medulla, reactive oxygen species, nitric oxide, oxidative stress, hypertension, fluid balance, renal sodium excretion, renal hemodynamics
- MeSH terms
- Blood Pressure, Diuresis, Endothelium, Vascular, Humans, Hydrogen Peroxide, Kidney Medulla, Natriuresis, Nitric Oxide, Sodium, Dietary, Superoxides, Water-Electrolyte Balance, Signal Transduction, Endothelins, Reactive Oxygen Species, Oxidative Stress, Nitric Oxide Synthase, Endothelium-Dependent Relaxing Factors
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