ABSTRACT: Aldose reductase (AR), the first and the rate-limiting enzyme of the polyol pathway, has been implicated in platelet-derived growth factor (PDGF)-induced proliferation of rat mesangial cells (MsCs). It is well known that AR plays an important role in various chronic diabetic complications, for example, diabetic nephropathy. Moreover, our previous studies have demonstrated that an AR inhibitor (ARI) significantly reduced the proliferation of rat MsCs induced by PDGF, however, the mechanism remains unclear. The aim of the present study was to elucidate the molecular mechanisms through which AR regulates PDGF-induced rat MsC proliferation. It was demonstrated that PDGF-induced MsC proliferation was significantly inhibited by pretreatment with ARI. Cell cycle analysis by flow cytometry revealed that ARI prevented the entry of cells from the G1 into the S phase. Furthermore, the effect of the PI3K/Akt signaling pathway on the cell cycle was analyzed. The PI3K/Akt pathway was activated with PDGF treatment. However, ARI blocked Akt activation in response to PDGF. Moreover, PDGF increased the levels of p21Cip1 cyclin kinase inhibitor protein in MsC, which was markedly inhibited by pretreatment with ARI. Conversely, PDGF significantly reduced the levels of the p27Kip1 cyclin kinase inhibitor protein, which was also restored by pretreatment with ARI. In conclusion, AR is involved in PDGF-induced rat MsC proliferation, and may serve as a potential target for the inhibition of MsC proliferation in several types of glomerulonephritis.
International Journal of Molecular Medicine 05/2012; 30(2):409-16. · 1.98 Impact Factor