Impact of obesity on renal structure and function in the presence and absence of hypertension: evidence from melanocortin-4 receptor-deficient mice
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The purpose of this study was to determine the long-term impact of obesity and related metabolic abnormalities in the absence and presence of hypertension on renal injury and salt-sensitivity of blood pressure. Markers of renal injury and blood pressure salt sensitivity were assessed in 52- to 55-wk-old normotensive melanocortin-4 receptor-deficient (MC4R-/-) mice and lean C57BL/6J wild-type (WT) mice and in 22-wk-old MC4R-/- and WT mice made hypertensive by N(G)-nitro-L-arginine methyl ester (L-NAME) in the drinking water for 8 wk. Old MC4R-/- mice were 60% heavier, hyperinsulinemic, and hyperleptinemic but had similar mean arterial pressure (MAP) as WT mice (115 +/- 2 and 117 +/- 2 mmHg) on normal salt diet (0.4% NaCl). A high-salt diet (4.0% NaCl) for 12 days did not raise MAP in obese or lean mice [DeltaMAP: MC4R (-/-) 4 +/- 2 mmHg; WT, 2 +/- 1 mmHg]. Obese MC4R-/- mice had 23% greater glomerular tuft area and moderately increased GFR compared with WT mice. Bowman's space, total glomerular area, mesangial matrix, urinary albumin excretion (UAE), renal TGF-beta and collagen expression were not significantly different between old MC4R-/- and WT mice. Renal lipid content was greater but renal macrophage count was markedly lower in MC4R-/- than WT mice. Mild increases in MAP during L-NAME treatment (approximately 16 mmHg) caused small, but greater, elevations in UAE, renal TGF-beta content, and macrophage infiltration in MC4R-/- compared with WT mice without significant changes in glomerular structure. Thus despite long-term obesity and multiple metabolic abnormalities, MC4R-/- mice have no evidence of renal injury or salt-sensitivity of blood pressure. These observations suggest that elevations in blood pressure may be necessary for obesity and related metabolic abnormalities to cause major renal injury or that MC4R-/- mice are protected from renal injury by mechanisms that are still unclear.
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MC4R appears to be the dominant efferent arm of the actions of the brain melanocortin system on regulation of food intake and body weight.
“Also, MC4R appears to be the dominant efferent arm of the actions of the brain melanocortin system on regulation of food intake and body weight [27, 28].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [28]
Leptin requires functional MC4R for most of its chronic cardiovascular and metabolic effects.
“Leptin requires functional MC4R for most of its chronic cardiovascular and metabolic effects.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [28]
Mice with whole-body MC4R deficiency are hyperphagic and obese, and have many characteristics of the metabolic syndrome including hyperglycemia, hyperinsulinemia, visceral adiposity and dyslipidemia despite markedly elevated blood leptin levels.
“Mice with whole-body MC4R deficiency are hyperphagic and obese, and have many characteristics of the metabolic syndrome including hyperglycemia, hyperinsulinemia, visceral adiposity and dyslipidemia despite markedly elevated blood leptin levels [27, 28, 52]; moreover, these mice are completely unresponsive to the effects of leptin to reduce appetite and to raise BP [27].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [28]
Leptin requires activation of POMC neurons and MC4R to mediate its effects on renal sympathetic nervous system activity and blood pressure.
“Leptin requires activation of POMC neurons and MC4R to mediate its effects on renal SNS activity and BP [28, 50, 51].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [28]
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- Authors
- do Carmo, J. M., Tallam, L. S., Roberts, J. V., Brandon, E. L., Biglane, J., da Silva, A. A., & Hall, J. E.
- ORCID
- Hall, John E.
- Venue
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
- Publisher
- American Physiological Society
- Published
- 2009-09
- Volume
- 297
- Issue
- 3
- Pages
- R803-R812
- ISSN
- 0363-6119 (ISSN-L)
- 1522-1490
- PMC
- PMC2739784
- OpenAlex
- W2159060689
- Cited by
- 50
- References
- 43
- Citations by year
- 2026: 1 · 2024: 2 · 2022: 3 · 2021: 3 · 2020: 2 · 2017: 5 · 2016: 3 · 2015: 7 · 2014: 4 · 2013: 7 · 2012: 1
- FWCI
- 3.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01-HL-51971, P01HL051971)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- obesity, kidney injury, hypertension, melanocortin-4 receptor, salt sensitivity of blood pressure, high-salt diet, glomerular structure, glomerular filtration rate, urinary albumin excretion, TGF-beta, renal macrophages, L-NAME-induced hypertension, hyperinsulinemia, hyperleptinemia
- MeSH terms
- Age Factors, Albuminuria, Animals, Blood Pressure, Body Weight, Disease Models, Animal, Glomerular Filtration Rate, Heart Rate, Hyperinsulinism, Hypertension, Kidney, Kidney Diseases, Mice, Inbred C57BL, Obesity, Biomarkers, Sodium Chloride, Dietary, Mice, Knockout, Leptin, Receptor, Melanocortin, Type 4, Mice
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