The Rho-family GTPases are powerful regulators of cellular signaling which controls cellular functions like gene expression, migration and inflammation. Activation of RhoA and Rac-1 has been linked to podocyte dysfunction, a feature of chronic kidney diseases. We investigated the effect of Rac-1 and Rho kinase (ROCK) inhibition on progressive renal failure in mice and studied the underlying mechanisms in cultured primary mouse podocytes.

The murine 5/6-nephrectomy model in SV129 mice was used which is characteristic by progressive arterial hypertension, glomerular dysfunction, and strong proteinuria. Subgroups were treated with Rac-1 and ROCK inhibitor. Application of both inhibitors markedly slowed kidney disease progression as evident by attenuated albumin excretion as well as lowered grade of glomerular and tubulointerstitial fibrosis. Blood pressure, in contrast, was not affected by the drugs. To simulate increased glomerular pressure we exposed podocytes to static stretch in the Flexercell device. Stretch activated small GTPases and led to podocyte dedifferentiation and TGFβ-mediated epithelial to mesenchymal transition, as evident from loss of podocyte markers (WT-1, nephrin) and acquisition of smooth muscle characteristics (αSMA, fibronectin expression). TGF beta also induced podocyte apoptosis. Application of Rac-1 as well as ROCK inhibiotors dramatically attenuated all these responses.

Taken together, these data suggest that activation of Rac-1 and RhoA is a critical step in podocyte dysfunction in progressive renal failure. Inhibitors of Rac-1 and ROCK activity with potentially minimal systemic side effects may be attractive candidates for the therapy of chronic kidney disease.