Activation of small GTPase Ras and renal fibrosis.

Although mechanisms responsible for the initiation and development of renal fibrosis have been extensively studied, the intracellular signals involved in this phenomenon are still poorly understood. Ras proteins are the prototype members of a large family of small GTPases bound to membrane that control signalling pathways implicated in cellular growth, differentiation, proliferation and apoptosis. The purpose of the present manuscript is to review Ras signalling studies focusing on the possible role of Ras activation in renal fibrosis. A cell-specific expression of the three Ras isoforms (K-Ras, H-Ras and N-Ras) has been found in both normal and injured kidneys. Ras activation has been described in cultured mesangial cells or renal fibroblasts when challenged with several cytokines, high glucose medium or advanced glycation end-products. A role for K-Ras has been demonstrated in renal fibroblast proliferation. Mesangial cell proliferation induced by high glucose can be reverted by 3-hydroxy-3-methylglutaryl CoA reductase inhibitor which blocks the synthesis of prenyl groups and consequently Ras activation. In addition, increased Ras activation measured by Ras-GTP/total Ras ratio has been found in an experimental model of tubulointerstitial fibrosis induced by unilateral ureteral ligation. In overall, these data give enough evidence of a role for Ras activation in renal fibrosis.