Renoprotective effects of combination of angiotensin converting enzyme inhibitor with mycophenolate mofetil in diabetic rats.
OBJECTIVE
Previously it was shown that blocking of the renin-angiotensin system (RAS) by angiotensin converting enzyme (ACE) inhibitors, or suppression of inflammatory responses by immunosuppressive drugs such as mycophenolate mofetil (MMF) could attenuate renal injury in diabetic rats. Whether RAS blockade combined with an immunosuppressive drug provides superior renoprotection against diabetic nephropathy has not been clearly delineated.


METHODS
Diabetes was induced by injection of streptozotocin after uninephrectomy.


METHODS
Rats were randomly separated into five groups: control, diabetes, diabetes treated with enalapril (an ACE inhibitor, 10 mg/kg/d by gastric gavage), diabetes treated with MMF (10 mg/kg/d by gastric gavage), or diabetes treated with a combination of both agents and were followed for 8 weeks.


METHODS
24 h urinary albumin excretion rate (AER) was determined, renal injury was evaluated, immunohistochemistry for ED-1 macrophage marker, intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) were performed, and expression of transforming growth factor (TGF)-beta1 protein was determined by Western blotting analysis.


RESULTS
Diabetes was associated with a considerable increase in AER. Both enalapril and MMF retarded the increase in albuminuria, which was nearly completely abrogated by combination therapy. Increased glomerular volume and tubulointerstitial injury index in diabetic rats was attenuated by treatment with either enalapril or MMF and further reduced by the combination of the two. Elevated malondialdehyde levels in renal tissue were reduced by enalapril or MMF and, more effectively, by combined enalapril with MMF. Renal overexpression of ICAM-1 was not retarded by enalapril and attenuated by MMF or combined enalapril with MMF. Combination therapy was associated with a superior suppression of diabetes-induced macrophage recruitment and overexpression of MCP-1 and TGFbeta1 compared to either monotherapy in renal tissue.


CONCLUSIONS
The combination of enalapril and MMF confers superiority over monotherapy in renoprotection, a mechanism which may be at least partly correlated with synergistic suppression of increased macrophage recruitment and overexpression of MCP-1 and TGF-beta1 in renal tissue in diabetic rats.
Wu
Y-G
YG
Department of Nephropathy, the First Affiliated Hospital of AnHui Medical University, 230022, Hefei, China. wygxll@ah163.com
Lin
H
H
Qian
H
H
Zhao
M
M
Qi
X-M
XM
Wu
G-Z
GZ
Lin
S-T
ST
D000419:Albuminuria / Q000188:drug therapy; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D000806:Angiotensin-Converting Enzyme Inhibitors; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D007166:Immunosuppressive Agents; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D018799:Intercellular Adhesion Molecule-1; D008315:Malondialdehyde; D004656:Enalapril; D009173:Mycophenolic Acid