Could mycophenolate mofetil combined with benazapril delay tubulointerstitial fibrosis in 5/6 nephrectomized rats?
BACKGROUND
It was reported that combination of mycophenolate mofetil (MMF) and enalapril could reduce proteinuria, improve renal function, and down-regulate diabetes-induced macrophage recruitment and expression of monocyte chemotactic protein 1 (MCP-1) and transforming growth factor beta (TGF-beta) in diabetic renal tissue. But there are no compelling data available for the combination of MMF and angiotensin converting enzyme inhibitor (ACEI) for suppressing tubulointerstitial fibrosis in chronic kidney diseases. The present study was to disclose the effect of MMF combined with benazapril on delaying tubulointerstitial fibrosis and its possible mechanisms in 5/6 nephrectomized rats.


METHODS
Fifty male SD rats underwent 5/6 nephrectomy (5/6 NX) were randomized into the following groups: NX (5/6 nephrectomized rats, distilled water, n = 10), MMF (MMF 20 mg x kg(-1) x d(-1), p.o., n = 10), Ben (benazepril 10 mg x kg(-1) x d(-1), p.o., n = 10), MMF/Ben (MMF 20 mg x kg(-1) x d(-1), p.o., and benazapril 10 mg x kg(-1) x d(-1), p.o., n = 10). They were monitored for proteinuria and systolic blood pressure every two weeks. After 8 weeks of treatment, serum creatinine and blood urea nitrogen were assayed and pathological damage to the kidney were evaluated. Renal expression and serum levels of platelet-derived growth factor-BB (PDGF-BB), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metaloproteinase-1 (TIMP-1) were detected by immunohistochemistry and ELISA methods.


RESULTS
After 8 weeks of treatment, 24-hour proteinuria, serum creatinine and blood urea nitrogen were significantly lower in treated groups compared with the untreated rats. MMF and benazepril combination therapy had a greater effect than either drug alone. MMF alone had no effect on systolic blood pressure, but benazapril and MMF/benazapril could significantly reduce blood pressure. Rats that underwent 5/6 nephrectomy had greater tubulointerstitial inflammatory cell infiltration and collagen accumulation than sham-operated rats; all treatments, especially MMF/benazepril, ameliorated these effects. Tubules in 5/6 nephrectomized rats expressed higher levels of PDGF-BB and TIMP-1 and lower MMP-9 compared with sham-operated rats. MMF and benazepril similarly reversed these phenomenons and combination therapy almost completely restored the expression of these cytokines in renal tissue and their plasma concentration.


CONCLUSIONS
MMF, especially combined with benazepril, can reduce proteinuria, improve renal function, ameliorate tubulointerstitial fibrosis in 5/6 nephrectomized rats. These effects might be, in part, associated with down-regulation of PDGF-BB and TIMP-1, and MMP-9 up-regulation in renal tissues.
Liu
Wen-hu
WH
Department of Nephrology, Affiliated Beijing Friendship Hospital of Capital Medical University, Beijing 100050, China. liuwh0211@yahoo.com.cn
Tang
Ni-na
NN
Zhang
Qi-dong
QD
D000818:Animals; D000077214:Becaplermin; D001552:Benzazepines / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009392:Nephrectomy; D009395:Nephritis, Interstitial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
D001552:Benzazepines; D007166:Immunosuppressive Agents; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D019715:Tissue Inhibitor of Metalloproteinase-1; D000077214:Becaplermin; D020780:Matrix Metalloproteinase 9; D009173:Mycophenolic Acid; C044946:benazepril