Mycophenolate mofetil inhibits hypertrophy and apoptosis of podocyte in vivo and in vitro.

OBJECTIVE: The present study aimed to examine the effect of mycophenolate mofetil (MMF), a new immunosuppressive agent, on hypertrophy and apoptosis of podocyte, and investigate the underlying mechanisms.

METHODS: Cultured rat podocyte were exposed to 5.6 mmol/L normal glucose or 25 mmol/L high glucose with mycophenolic acid (MPA) or Valsartan for 72 h. For animal studies, streptozotocin-induced diabetic rats were untreated or treated with MMF or Valsartan for 16 weeks. After 16 weeks of treatment, the weight of kidney and body, 24 hours urinary protein excretion and serum glucose was detected. Histomorphology of renal tissue was observed by optical microscope and electron microscope. Apoptosis of podocytes were determined by transferase-mediated dUTP nick-end labeling (TUNEL) test. The protein expressions of p21(cip1), p27(kip1), bax and bcl-2 were examined by Western blot.

RESULTS: p27(kip1), p21(cip1) protein expression in podocytes exposed to high glucose for 72 h and in 16 weeks diabetic glomeruli significantly increased (P<0.01). The expressions of bax, cleaved caspase-3 increased while the expression of bcl-2 decreased in diabetic glomeruli as well as in high glucose. But they were all ameliorated in the groups treated with either MMF or Valsartan.

CONCLUSION: MMF can inhibit abnormal hypertrophy and apoptosis of podocytes in the early stage of diabetes, partly by regulating the expression of cell cycle related protein p27(kip1), p21(cip1) and apoptosis related genes, such as bax, bcl-2 and cleaved caspase-3. These suggest that the protective effects of MMF on renal function maybe partly through inhibiting abnormal renal cell growth by regulating cell cycle or apoptosis related genes.