Protective role of cGMP/cGKI in kidney fibrosis

抄録

Kidney fibrosis is predominantly involved in the generation of chronic kidney diseases (CKD). However, there are only few therapeutics available for the suppression of kidney fibrosis and the treatment of CKD. Hence, the elucidation of new signalling pathways interfering with kidney fibrosis is needed. cGMP signalling was previously uncovered to affect renal fibrotic diseases. To study the effective signal transduction pathways of cGMP we studied whether the cGMP-dependent protein kinase cGKI acts antifibrotically in the kidney.

We localized the expression of the cGKIalpha isozyme in the renal medullary interstitium. The role of cGKI in the kidney fibrosis was analysed using unilateral ureteral obstruction (UUO) in wild type and cGKI-KO mice. We tested whether the pharmacological stimulation of the cGMP/cGKI signalling pathway affects the induction of interstitial kidney fibrosis. For this purpose we used a) NO-independent sGC stimulators (YC-1, Bay41-8543), b) the pregnancy hormone Serelaxin which was shown to provoke cGMP levels and c) a combination of Serelaxin with the PDE5 inhibitor zaprinast which reduces the cGMP degradation. sGC stimulators intensely reduced TGFbeta levels, differentiation of myofibroblasts and deposition of extracellular matrix proteins (collagen, fibronectin) in wild type mice involving signalling by RhoA/ROCK and by MAP-kinases Erk1/2 in contrast to cGKI-KO. Serelaxin administration leads to enhanced cGMP concentrations in the kidney. Treatment with Serelaxin also effectively decreased interstitial kidney fibrosis via diminished cytokines (TGFbeta, CTGF), myofibroblasts and ECM and by regulation of matrix metalloproteases (MMP-2, MMP-9) dependent on the presence of cGKI. However, our results indicated that Serelaxin might use different signalling pathways via Smad2 and Erk1. The PDE5-inhibitor zaprinast reduced the kidney fibrosis by Erk1/2 signalling, but independent of cGKI. The combination of Serelaxin and zaprinast did not reveal an additive antifibrotic effect.

In conclusion, sGC stimulators, PDE5 inhibitors or Serelaxin suppress interstitial kidney fibrosis via cGMP/cGKI signalling and might lead to further pharmacological options for the treatment of CKD.

Acknowledgements

The research project was supported by DFG-SFB699 and Novartis Pharma GmbH (Nuremberg). Bay41-8543 and Serelaxin was provided by Bayer Pharma AG (Berlin) and Novartis AG (Basel), respectively.