Valsartan inhibits amylin-induced podocyte damage.
Previous studies have described the deposition of amylin in the kidney of patients with type 2 diabetes mellitus (T2DM). These deposits play a critical role in the pathogenesis of diabetic nephropathy (DN), although the mechanism underlying this effect is unknown. Thus, this study was undertaken to investigate whether amylin aggregation stimulates the local angiotensin II type 1 receptor (AT1R) in podocytes, and to examine its role in podocyte apoptosis. Amylin-induced apoptosis was investigated in vitro in differentiated, conditionally immortalized mouse podocytes and in vivo in KM mice. Expression of genes including nephrin, podocin, AT1R and desmin was measured through quantitative real time PCR, western blot and immunohistochemistry. Apoptosis was determined by flow cytometry, while the cellular distribution of podocin and nephrin was investigated by immunofluorescence. The ultra-structure of glomeruli was examined by transmission electron microscopy (TEM). Amylin enhanced apoptosis in a dose-dependent manner in vitro. The peptide also suppressed podocin and nephrin expression, but enhanced that of AT1R and desmin. Both effects were significantly blocked by valsartan, which inhibits angiotensin II type 1 receptor. These findings suggest that amylin activates a local intracellular RAS in podocytes and induces damage and apoptosis.
Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Fengjuan
F
Huang
Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Qingzhu
Q
Wang
Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Xiaojun
X
Ma
Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Lina
L
Wu
Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Feng
F
Guo
Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. Electronic address: hyqingj@zzu.edu.cn.
Guijun
G
Qin
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D019610:Cytoprotection; D003893:Desmin / Q000235:genetics / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D058228:Islet Amyloid Polypeptide / Q000633:toxicity*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D046529:Microscopy, Electron, Transmission; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D060888:Real-Time Polymerase Chain Reaction; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects*; D000068756:Valsartan / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D003893:Desmin; D047908:Intracellular Signaling Peptides and Proteins; D058228:Islet Amyloid Polypeptide; D008565:Membrane Proteins; C407223:NPHS2 protein; D044140:Receptor, Angiotensin, Type 1; C113267:nephrin; D000068756:Valsartan
AT1R; Amylin; Diabetic nephropathy; Podocyte