Abstract
Rho-family GTPases like RhoA and Rac-1 are potent regulators of cellular signaling that control gene expression, migration and inflammation. Activation of Rho-GTPases has been linked to podocyte dysfunction, a feature of chronic kidney diseases (CKD). We investigated the effect of Rac-1 and Rho kinase (ROCK) inhibition on progressive renal failure in mice and studied the underlying mechanisms in podocytes. SV129 mice were subjected to 5/6-nephrectomy which resulted in arterial hypertension and albuminuria. Subgroups of animals were treated with the Rac-1 inhibitor EHT1846, the ROCK inhibitor SAR407899 and the ACE inhibitor Ramipril. Only Ramipril reduced hypertension. In contrast, all inhibitors markedly attenuated albumin excretion as well as glomerular and tubulo-interstitial damage. The combination of SAR407899 and Ramipril was more effective in preventing albuminuria than Ramipril alone. To study the involved mechanisms, podocytes were cultured from SV129 mice and exposed to static stretch in the Flexcell device. This activated RhoA and Rac-1 and led via TGFβ to apoptosis and a switch of the cells into a more mesenchymal phenotype, as evident from loss of WT-1 and nephrin and induction of α-SMA and fibronectin expression. Rac-1 and ROCK inhibition as well as blockade of TGFβ dramatically attenuated all these responses. This suggests that Rac-1 and RhoA are mediators of podocyte dysfunction in CKD. Inhibition of Rho-GTPases may be a novel approach for the treatment of CKD.
Highlights
Chronic renal failure is a self-perpetuating process of different etiology, which may lead to end-stage renal failure and renal replacement therapy
To investigate the contribution of the small GTPases Rac-1 and RhoA to the processes leading to progressive chronic renal failure, the 5/6Nx mice and their sham operated counterparts were treated with a set of inhibitors: the HMGCoA reductase inhibitor Rosuvastatin, the ACE inhibitor Ramipril, the Rac-1 inhibitor EHT1864 and the ROCK inhibitor SAR407899
ACE inhibition was superior to Rac-1 or ROCK inhibition in preventing albuminuria but coadministration of the ROCK inhibitor to the ACE inhibitor exerted a significant add on protective effect after 8 weeks (Figure 1A&B)
Summary
Chronic renal failure is a self-perpetuating process of different etiology, which may lead to end-stage renal failure and renal replacement therapy. Numerous conditions such as diabetes mellitus, hypertension, glomerulonephritis and preexistent structural renal abnormalities can initiate chronic kidney disease. Tubulo-interstitial fibrosis is commonly present with increased inflammatory activation of the renal tissue and deposition of matrix. These processes result in loss of active nephrons so that the remaining nephrons including their glomeruli undergo compensatory hypertrophy [2,3]
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