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AuthorMunusamy, Shankar
Authordo Carmo, Jussara M.
AuthorHosler, Jonathan P.
AuthorHall, John E.
Available date2016-11-07T07:31:48Z
Publication Date2015-10-15
Publication NameAJP - Renal Physiologyen_US
CitationMunusamy S, do Carmo JM, Hosler JP, Hall JE. Obesity-induced changes in kidney mitochondria and endoplasmic reticulum in the presence or absence of leptin. American Journal of Physiology - Renal Physiology. 2015;309(8):F731-F743.
AbstractWe investigated obesity-induced changes in kidney lipid accumulation, mitochondrial function, and endoplasmic reticulum (ER) stress in the absence of hypertension, and the potential role of leptin in modulating these changes. We compared two normotensive genetic mouse models of obesity, leptin-deficient ob/ob mice and hyperleptinemic melanocortin-4 receptor-deficient mice (LoxTB MC4R−/−), with their respective lean controls. Compared with controls, ob/ob and LoxTB MC4R−/− mice exhibit significant albuminuria, increased creatinine clearance, and high renal triglyceride content. Renal ATP levels were decreased in both obesity models, and mitochondria isolated from both models showed alterations that would lower mitochondrial ATP production. Mitochondria from hyperleptinemic LoxTB MC4R−/− mice kidneys respired NADH-generating substrates (including palmitate) at lower rates due to an apparent decrease in complex I activity, and these mitochondria showed oxidative damage. Kidney mitochondria of leptin-deficient ob/ob mice showed normal rates of respiration with no evidence of oxidative damage, but electron transfer was partially uncoupled from ATP synthesis. A fourfold induction of C/EBP homologous protein (CHOP) expression indicated induction of ER stress in kidneys of hyperleptinemic LoxTB MC4R−/− mice. In contrast, ER stress was not induced in kidneys of leptin-deficient ob/ob mice. Our findings show that obesity, in the absence of hypertension, is associated with renal dysfunction in mice but not with major renal injury. Alterations to mitochondria that lower cellular ATP levels may be involved in obesity-induced renal injury. The type and severity of mitochondrial and ER dysfunction differs depending upon the presence or absence of leptin.
SponsorNational Heart, Lung, and Blood Institute Grant (PO1HL51971), the National Institute of General Medical Sciences (P20GM104357), and an American Heart Association (Greater Southeast Affiliate) Postdoctoral Fellowship Grant (09POST2300079) to S. Munusamy and a Scientist Development Grant (AHA58161) to J. M. do Carmo.
PublisherAmerican Physiological Society
Subjectendoplasmic reticulum stress
Subjectmelanocortin-4 receptor (MC4R)
TitleObesity-induced changes in kidney mitochondria and endoplasmic reticulum in the presence or absence of leptin
Issue Number8
Volume Number309

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