title: Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: possible contribution of fat-derived factors.
abstract: Metabolic syndrome is an important risk factor for proteinuria and chronic kidney disease independent of diabetes and hypertension; however, the underlying mechanisms have not been elucidated. Aldosterone is implicated in target organ injury of obesity-related disorders. This study investigated the role of aldosterone in the early nephropathy of 17-wk-old SHR/NDmcr-cp, a rat model of metabolic syndrome. Proteinuria was prominent in SHR/NDmcr-cp compared with nonobese SHR, which was accompanied by podocyte injury as evidenced by foot process effacement, induction of desmin and attenuation of nephrin. Serum aldosterone level, renal and glomerular expressions of aldosterone effector kinase Sgk1, and oxidative stress markers all were elevated in SHR/NDmcr-cp. Mineralocorticoid receptors were expressed in glomerular podocytes. Eplerenone, a selective aldosterone blocker, effectively improved podocyte damage, proteinuria, Sgk1, and oxidant stress. An antioxidant tempol also alleviated podocyte impairment and proteinuria, along with inhibition of Sgk1. As for the mechanisms of aldosterone excess, visceral adipocytes that were isolated from SHR/NDmcr-cp secreted substances that stimulate aldosterone production in adrenocortical cells. The aldosterone-releasing activity of adipocytes was not inhibited by candesartan. Adipocytes from nonobese SHR did not show such activity. In conclusion, SHR/NDmcr-cp exhibit enhanced aldosterone signaling, podocyte injury, and proteinuria, which are ameliorated by eplerenone or tempol. The data also suggest that adipocyte-derived factors other than angiotensin II might contribute to the aldosterone excess of this model.
authors.affiliation: Department of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. mnagase-tky@umin.ac.jp
authors.forename: Miki
authors.initials: M
authors.lastname: Nagase
authors.forename: Shigetaka
authors.initials: S
authors.lastname: Yoshida
authors.forename: Shigeru
authors.initials: S
authors.lastname: Shibata
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagase
authors.forename: Takanari
authors.initials: T
authors.lastname: Gotoda
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Ando
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
mesh_terms: D017667:Adipocytes; D000311:Adrenal Glands / Q000378:metabolism; D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D000077545:Eplerenone; D017874:Immediate-Early Proteins / Q000187:drug effects / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000209:etiology* / Q000473:pathology; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism* / Q000473:pathology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009765:Obesity / Q000150:complications*; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011507:Proteinuria / Q000150:complications / Q000652:urine; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D013113:Spin Labels; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000450:Aldosterone; D003497:Cyclic N-Oxides; D000077545:Eplerenone; D017874:Immediate-Early Proteins; D000451:Mineralocorticoid Receptor Antagonists; D017346:Protein Serine-Threonine Kinases; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D013113:Spin Labels; D013148:Spironolactone; D000099184:Serum-Glucocorticoid Regulated Kinases; C001803:tempol