Telmisartan Ameliorates Nephropathy in Metabolic Syndrome by Reducing Leptin Release From Perirenal Adipose Tissue.
Metabolic syndrome (MetS) is associated with nephropathy. Along with common risk factors such as hypertension and hyperglycemia, adipocytokines released from perirenal adipose tissue (PRAT) are implicated in the pathogenesis of MetS nephropathy. The study was designed to elucidate the adverse effects of PRAT-derived leptin on nephropathy and to determine whether the angiotensin II type 1 receptor antagonist telmisartan exerts a renoprotective effect by decreasing the PRAT-derived leptin level in the high-fat diet-induced MetS rat. In MetS rats, PRAT-derived leptin expression increased concomitant with dysfunction of adipogenesis, and the activities of the angiotensin II-angiotensin II type 1 receptor and the angiotensin-converting enzyme 2-angiotensin (1-7)-Mas receptor axes were imbalanced in PRAT. PRAT-derived leptin from MetS rats promoted proliferation of rat glomerular endothelial cells (GERs) by activating the p38 MAPK (mitogen-activated protein kinase) pathway, thereby contributing to the development of nephropathy. Long-term telmisartan treatment improved metabolic parameters and renal function, decreased the amount of PRAT, promoted adipogenesis, increased the expression of angiotensin-converting enzyme 2, restored balanced activities of the angiotensin II-AT1R and angiotensin-converting enzyme 2-angiotensin (1-7)-Mas axes, and exerted an indirect renoprotective effect on MetS rats by decreasing PRAT-derived leptin release. Our results demonstrate a novel link between nephropathy and PRAT in MetS and show that telmisartan confers an underlying protective effect on visceral adipose tissue and the kidney, suggesting that it has potential as a therapeutic agent for the treatment of MetS-associated nephropathy.
From the Department of Critical Care Medicine (H.L., L.G.), Department of Cardiology (M.L., H.Z., H.L., Y.Y., S.C., G.T.), Department of Nephrology (S.Y.), and Department of Ultrasound Medicine (Y.S.), The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China; Department of Endocrinology, The Affiliated Xi'an Central Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, P.R. China (P.L.); Department of Geriatric Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, P. R. China (Y.W.); Hypertension Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College (J.C.); and Key Laboratory of Shaanxi Province on Molecular Cardiology and Key Laboratory of Ministry of Education of People's Republic of China on Environment and Genes Related to Diseases, Xi'an, Shaanxi, P. R. China (H.L., G.T.).
Hao
H
Li
From the Department of Critical Care Medicine (H.L., L.G.), Department of Cardiology (M.L., H.Z., H.L., Y.Y., S.C., G.T.), Department of Nephrology (S.Y.), and Department of Ultrasound Medicine (Y.S.), The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China; Department of Endocrinology, The Affiliated Xi'an Central Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, P.R. China (P.L.); Department of Geriatric Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, P. R. China (Y.W.); Hypertension Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College (J.C.); and Key Laboratory of Shaanxi Province on Molecular Cardiology and Key Laboratory of Ministry of Education of People's Republic of China on Environment and Genes Related to Diseases, Xi'an, Shaanxi, P. R. China (H.L., G.T.).
Min
M
Li
From the Department of Critical Care Medicine (H.L., L.G.), Department of Cardiology (M.L., H.Z., H.L., Y.Y., S.C., G.T.), Department of Nephrology (S.Y.), and Department of Ultrasound Medicine (Y.S.), The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China; Department of Endocrinology, The Affiliated Xi'an Central Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, P.R. China (P.L.); Department of Geriatric Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, P. R. China (Y.W.); Hypertension Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College (J.C.); and Key Laboratory of Shaanxi Province on Molecular Cardiology and Key Laboratory of Ministry of Education of People's Republic of China on Environment and Genes Related to Diseases, Xi'an, Shaanxi, P. R. China (H.L., G.T.).
Ping
P
Liu
From the Department of Critical Care Medicine (H.L., L.G.), Department of Cardiology (M.L., H.Z., H.L., Y.Y., S.C., G.T.), Department of Nephrology (S.Y.), and Department of Ultrasound Medicine (Y.S.), The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China; Department of Endocrinology, The Affiliated Xi'an Central Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, P.R. China (P.L.); Department of Geriatric Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, P. R. China (Y.W.); Hypertension Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College (J.C.); and Key Laboratory of Shaanxi Province on Molecular Cardiology and Key Laboratory of Ministry of Education of People's Republic of China on Environment and Genes Related to Diseases, Xi'an, Shaanxi, P. R. China (H.L., G.T.).
YaPing
Y
Wang
From the Department of Critical Care Medicine (H.L., L.G.), Department of Cardiology (M.L., H.Z., H.L., Y.Y., S.C., G.T.), Department of Nephrology (S.Y.), and Department of Ultrasound Medicine (Y.S.), The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China; Department of Endocrinology, The Affiliated Xi'an Central Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, P.R. China (P.L.); Department of Geriatric Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, P. R. China (Y.W.); Hypertension Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College (J.C.); and Key Laboratory of Shaanxi Province on Molecular Cardiology and Key Laboratory of Ministry of Education of People's Republic of China on Environment and Genes Related to Diseases, Xi'an, Shaanxi, P. R. China (H.L., G.T.).
Heng
H
Zhang
From the Department of Critical Care Medicine (H.L., L.G.), Department of Cardiology (M.L., H.Z., H.L., Y.Y., S.C., G.T.), Department of Nephrology (S.Y.), and Department of Ultrasound Medicine (Y.S.), The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China; Department of Endocrinology, The Affiliated Xi'an Central Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, P.R. China (P.L.); Department of Geriatric Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, P. R. China (Y.W.); Hypertension Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College (J.C.); and Key Laboratory of Shaanxi Province on Molecular Cardiology and Key Laboratory of Ministry of Education of People's Republic of China on Environment and Genes Related to Diseases, Xi'an, Shaanxi, P. R. China (H.L., G.T.).
HongBin
H
Li
From the Department of Critical Care Medicine (H.L., L.G.), Department of Cardiology (M.L., H.Z., H.L., Y.Y., S.C., G.T.), Department of Nephrology (S.Y.), and Department of Ultrasound Medicine (Y.S.), The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China; Department of Endocrinology, The Affiliated Xi'an Central Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, P.R. China (P.L.); Department of Geriatric Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, P. R. China (Y.W.); Hypertension Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College (J.C.); and Key Laboratory of Shaanxi Province on Molecular Cardiology and Key Laboratory of Ministry of Education of People's Republic of China on Environment and Genes Related to Diseases, Xi'an, Shaanxi, P. R. China (H.L., G.T.).
ShiFeng
S
Yang
From the Department of Critical Care Medicine (H.L., L.G.), Department of Cardiology (M.L., H.Z., H.L., Y.Y., S.C., G.T.), Department of Nephrology (S.Y.), and Department of Ultrasound Medicine (Y.S.), The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China; Department of Endocrinology, The Affiliated Xi'an Central Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, P.R. China (P.L.); Department of Geriatric Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, P. R. China (Y.W.); Hypertension Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College (J.C.); and Key Laboratory of Shaanxi Province on Molecular Cardiology and Key Laboratory of Ministry of Education of People's Republic of China on Environment and Genes Related to Diseases, Xi'an, Shaanxi, P. R. China (H.L., G.T.).
Yan
Y
Song
From the Department of Critical Care Medicine (H.L., L.G.), Department of Cardiology (M.L., H.Z., H.L., Y.Y., S.C., G.T.), Department of Nephrology (S.Y.), and Department of Ultrasound Medicine (Y.S.), The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China; Department of Endocrinology, The Affiliated Xi'an Central Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, P.R. China (P.L.); Department of Geriatric Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, P. R. China (Y.W.); Hypertension Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College (J.C.); and Key Laboratory of Shaanxi Province on Molecular Cardiology and Key Laboratory of Ministry of Education of People's Republic of China on Environment and Genes Related to Diseases, Xi'an, Shaanxi, P. R. China (H.L., G.T.).
YanRong
Y
Yin
From the Department of Critical Care Medicine (H.L., L.G.), Department of Cardiology (M.L., H.Z., H.L., Y.Y., S.C., G.T.), Department of Nephrology (S.Y.), and Department of Ultrasound Medicine (Y.S.), The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China; Department of Endocrinology, The Affiliated Xi'an Central Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, P.R. China (P.L.); Department of Geriatric Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, P. R. China (Y.W.); Hypertension Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College (J.C.); and Key Laboratory of Shaanxi Province on Molecular Cardiology and Key Laboratory of Ministry of Education of People's Republic of China on Environment and Genes Related to Diseases, Xi'an, Shaanxi, P. R. China (H.L., G.T.).
Lan
L
Gao
From the Department of Critical Care Medicine (H.L., L.G.), Department of Cardiology (M.L., H.Z., H.L., Y.Y., S.C., G.T.), Department of Nephrology (S.Y.), and Department of Ultrasound Medicine (Y.S.), The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China; Department of Endocrinology, The Affiliated Xi'an Central Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, P.R. China (P.L.); Department of Geriatric Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, P. R. China (Y.W.); Hypertension Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College (J.C.); and Key Laboratory of Shaanxi Province on Molecular Cardiology and Key Laboratory of Ministry of Education of People's Republic of China on Environment and Genes Related to Diseases, Xi'an, Shaanxi, P. R. China (H.L., G.T.).
Si
S
Cheng
From the Department of Critical Care Medicine (H.L., L.G.), Department of Cardiology (M.L., H.Z., H.L., Y.Y., S.C., G.T.), Department of Nephrology (S.Y.), and Department of Ultrasound Medicine (Y.S.), The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China; Department of Endocrinology, The Affiliated Xi'an Central Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, P.R. China (P.L.); Department of Geriatric Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, P. R. China (Y.W.); Hypertension Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College (J.C.); and Key Laboratory of Shaanxi Province on Molecular Cardiology and Key Laboratory of Ministry of Education of People's Republic of China on Environment and Genes Related to Diseases, Xi'an, Shaanxi, P. R. China (H.L., G.T.).
Jun
J
Cai
From the Department of Critical Care Medicine (H.L., L.G.), Department of Cardiology (M.L., H.Z., H.L., Y.Y., S.C., G.T.), Department of Nephrology (S.Y.), and Department of Ultrasound Medicine (Y.S.), The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China; Department of Endocrinology, The Affiliated Xi'an Central Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, P.R. China (P.L.); Department of Geriatric Cardiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi, P. R. China (Y.W.); Hypertension Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College (J.C.); and Key Laboratory of Shaanxi Province on Molecular Cardiology and Key Laboratory of Ministry of Education of People's Republic of China on Environment and Genes Related to Diseases, Xi'an, Shaanxi, P. R. China (H.L., G.T.).
Gang
G
Tian
D050156:Adipogenesis / Q000187:drug effects* / Q000502:physiology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D004195:Disease Models, Animal; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D020738:Leptin / Q000009:adverse effects / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications* / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000077333:Telmisartan
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D020738:Leptin; D020011:Protective Agents; D000077333:Telmisartan
adipocytes; angiotensin-converting enzyme 2; leptin; obesity; telmisartan