Activation of Rac-1 and RhoA contributes to podocyte injury in chronic kidney disease.
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.
Physiology I, Goethe-University, Frankfurt am Main, Germany.
Andrea
A
Babelova
Felix
F
Jansen
Kerstin
K
Sander
Matthias
M
Löhn
Liliana
L
Schäfer
Christian
C
Fork
Hartmut
H
Ruetten
Oliver
O
Plettenburg
Holger
H
Stark
Christoph
C
Daniel
Kerstin
K
Amann
Hermann
H
Pavenstädt
Oliver
O
Jung
Ralf P
RP
Brandes
D000419:Albuminuria / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D007546:Isoquinolines / Q000627:therapeutic use; D008297:Male; D051379:Mice; D010880:Piperidines / Q000627:therapeutic use; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism*; D011753:Pyrones / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use; D017257:Ramipril / Q000627:therapeutic use; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
C506907:EHT 1864; D007546:Isoquinolines; D010880:Piperidines; D011753:Pyrones; D011804:Quinolines; C000592760:SAR407889A; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D017257:Ramipril