Epigenetic RASAL1 silencing in renal fibrogenesis

• Applicant: Professor Dr. Michael Zeisberg
• Subject Area: Nephrology
• Term: from 2014 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 261661847

As the progression of chronic kidney disease remains an unsolved problem in Nephrology, there remains a pressing need to understand molecular mechanisms of renal fibrogenesis with the ultimate goal to develop novel therapeutic strategies. In this regard we previously demonstrated that the epigenetic mechanism of aberrant promoter CpG island methylation of specific genes contributes to fibroblast activation and that fibrogenesis in the kidney is associated with aberrant DNA hypermethylation (Nature Medicine 2010). As one gene affected by aberrant promoter-methylation we identified RASAL1, an inhibitor of Ras-GTP, and we demonstrated that renal fibrosis is associated with RASAL1 hypermethylation and its subsequent transcriptional suppression, irrespective of the underlying disease (JASN 2014). In direct extension of our previous work, studies proposed in this application will now elucidate the causal contribution of RASAL1 depletion to progression of renal fibrogenesis and decipher the molecular mechanisms which elicit fibroblast activation upon RASAL1 silencing. For this purpose we have now successfully generated two new mouse strains, one which harbors floxed Rasal1 alleles for conditional ablation and also rtTAhCMV;hRASAL1-pTreTight double-trangenic mice for methylation-resistant RASAL1-overexpression, which will serve as foundation for our studies. Successful completion of proposed research will provide novel mechanistic insights into the biological function of RASAL1 and also into the Ras effector pathways, which are involved in renal fibrogenesis. Such knowledge may enable targeted utillization of Ras-GTP and Ras-effector pathway inhibitors which have been developed in the cancer field to possibly ameliorate renal fibrosis in the future.

• DFG Programme: Research Grants