Effects of mycophenolate mofetil, valsartan and their combined therapy on preventing podocyte loss in early stage of diabetic nephropathy in rats.
BACKGROUND
Podocyte has inflammatory role in the development of diabetic nephropathy (DN). Mycophenolate mofetil (MMF), an anti-inflammatory agent, can suppress macrophage infiltration and reduce renal injury in streptozotocin-induced diabetic rats. Angiotensin II receptor blocker (ARB), another renal protecting agent, can decrease podocyte loss in DN. In this study, we detected the expression levels of monocyte chemoattractant protein-1 (MCP-1) and nephrin to evaluate podocyte's role in inflammatory reaction in DN, observe and compare the effect of MMF alone and in combination with valsartan, on preventing podocyte loss in streptozotocin (STZ) induced diabetic rats.


METHODS
Diabetic model was constructed in uninephrectomized male Wistar rats by single peritoneal injection of STZ (65 mg/kg). The successfully induced diabetic rats were randomly divided into four groups: diabetes without treatment group (DM), valsartan treated group (DMV), MMF treated group (DMM), and combined therapy group (DMVM). Normal rats of the same sibling were chosen as control (NC). At the end of the 8th week, serum biochemistry, 24-hour urinary protein (UP) and the ratio of kidney weight/body weight (RWK/B) were measured. The rats were sacrificed for the observation of renal histomorphology through light and electron microscope. Nephrin, desmin and MCP-1 levels were detected by semi-quantitative immunohistochemical assays. Real-time quantitative PCR was used to detect the mRNA levels of nephrin and MCP-1.


RESULTS
Compared with group NC, serum glucose level, 24-hour UP and RWK/B in group DM were significantly higher (P < 0.01), and the nephrin mRNA level in DM group was significantly lower (P < 0.05). The nephrin mRNA expression levels in group DMV, DMM and DMVM were all higher than that of DM group (P < 0.05) and no significant differences were found among the three treatment groups (P > 0.05). Treatment with MMF, valsartan or their combination could significantly decrease the 24-hour UP and RWK/B, and suppress glomerulosclerosis and interstitial fibrotic lesions in diabetic rats. In diabetic rats, the high expressions of desmin and MCP-1 in kidney were suppressed by valsartan, MMF or their combination.


CONCLUSIONS
Podocytes are involved in the inflammatory reaction of diabetic rats. MMF could suppress MCP-1 and desmin expression, enhance nephrin expression, and attenuate proteinuria in diabetic rats. The combined therapy of valsartan and MMF did not show any superiority over monotherapies on renal protection. MMF may have renoprotective effect in early stages of diabetic nephropathy through preventing podocytes loss and anti-inflammatory activity.
Zhang
Yan
Y
Department of Nephrology, Second Hospital of Shandong University, Jinan 250033, China.
Chen
Bing
B
Hou
Xiang-hua
XH
Guan
Guang-ju
GJ
Liu
Gang
G
Liu
Hai-ying
HY
Li
Xue-gang
XG
D000818:Animals; D018932:Chemokine CCL2 / Q000032:analysis; D003893:Desmin / Q000032:analysis; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000473:pathology; D004359:Drug Therapy, Combination; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D050199:Podocytes / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068756:Valsartan
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D003893:Desmin; D008565:Membrane Proteins; D013777:Tetrazoles; C113267:nephrin; D000068756:Valsartan; D014633:Valine; D009173:Mycophenolic Acid