Prevention of early renal injury by mycophenolate mofetil and its mechanism in experimental diabetes.
Previously it was shown that treatment with mycophenolate mofetil (MMF) attenuated renal inflammation and glomerular injury in a model of diabetes. However, the mechanism involved in the renoprotective effects of MMF in experimental diabetes has not been clearly delineated. Diabetes was induced by injection of streptozotocin (STZ) after uninephrectomy. Diabetic animals received no treatment or treatment with MMF (10 mg/kg once daily by gastric gavage) for 8 weeks, non-diabetic rats served as controls. Level of malondialdehyde (MDA) in renal tissue and urine as well as the activity of antioxidant enzymes (AOE) in renal tissue was determined. Renal injury was evaluated. Immunohistochemistry for ED-1 macrophages marker, intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) was performed. Expression of transforming growth factor (TGF)-beta1 protein was determined by Western blotting analysis. Treatment with MMF had no effect on blood glucose level, but did prevent increased urinary albumin excretion and glomerular damage in diabetic rats. Oxidative stress was reduced by MMF treatment, as indicated by a reduction in MDA level in renal tissue and urine. Activity of AOE such as glutathione peroxidase (GSH-PX) was markedly elevated while superoxide dismutase (SOD) and catalase (CAT) were not changed by MMF treatment. In diabetic animals receiving no treatment, there were increases in ED-1-positive cells, ICAM-1 expression and MCP-1 expression in glomeruli and tubulointerstitium, which were effectively suppressed by MMF treatment. Western blotting analysis showed that the expression of TGF-beta1 protein was increased by 1.92-fold in renal tissue in diabetic rats, and MMF treatment significantly reduced the increased expression of TGF-beta1 protein by 45%. Our data suggest that MMF treatment ameliorates early renal injury via the inhibition of oxidative stress and overexpression of ICAM-1, MCP-1 and TGF-beta1 in renal tissue in diabetic rats.
Wu
Yong-Gui
YG
Department of Nephropathy, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China. wygxll@ah163.com
Lin
Hui
H
Qi
Xiang-Ming
XM
Wu
Guo-Zhong
GZ
Qian
Hao
H
Zhao
Min
M
Shen
Ji-Jia
JJ
Lin
Shan-Tan
ST
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000473:pathology; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D053773:Transforming Growth Factor beta1; D018799:Intercellular Adhesion Molecule-1; D009173:Mycophenolic Acid