Molecular determinants of progression of chronic kidney disease

• Applicant: Professor Dr. Michael Zeisberg
• Subject Area: Nephrology
• Term: from 2012 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 225771312

Progression of chronic kidney disease (CKD) leading to end-stage renal disease (ESRD) remains a principal problem in nephrology. Specific therapies to halt, or even reverse progression of CKD are not yet available. Furthermore, it is not yet understood why the progression rate of CKD varies substantially, even among patients with identical underlying diseases. Studies proposed in this application are focused on the role of eyes absent homolog 1 (EYA1) in the progression of CKD. While EYA1 is known as an important determinant of kidney development, its role in the adult kidney has not yet been explored. Unlike in other species where only one Eya1 transcript exists, EYA1 in humans is subject to alternate splicing, generating distinct transcript variants. Our preliminary studies demonstrate that progression of CKD is associated with decreased expression of transcript variant EYA1C (the predominant isoform in normal kidney), whereas EYA1A is increased (“Isoform switch”). Our studies further demonstrated that EYA1A causally enhances fibroblast proliferation and fibrogenesis, whereas EYA1C was reno-protective. Furthermore, our studies revealed that EYA1A acts predominantly as tyrosine phosphatase on its sole substrate histone gammaH2A.X, whereas EYA1C functions as transcriptional activator. We also observed that the intronic single-nucleotide polymorphism SNP rs13259388 favored generation of the pro-fibrotic isoform EYA1A. In addition we found that among CKD patients, bi-allelic SNP carriers had an increased risk to require renal replacement therapy over a 10-year observational period. Studies proposed in this continuation-application will for the first time explore the biology of distinct EYA1 transcript variants. Due to its pro-fibrotic activity, studies planned here will primarily focus on EYA1 isoform A in context of chronic kidney disease. Specifically, studies will elucidate mechanisms which underlie the detrimental isoform switch and will also explore the mechanisms through which EYA1 SNP13259388 impacts alternative splicing (Specific aim 1). Studies will also explore mechanisms which underlie the contribution of EYA1A to progression of CKD. Specifically, studies will analyze impact of gammaH2A.X dephosphorylation on fibroblast proliferation and DNA damage responses (Specific aim 2). In summary, successful completion of proposed experiments will for the first time establish evidence for distinct biological activities of EYA1 splice variants and establish mechanistic insights how this contributes to progression of chronic kidney disease.

• DFG Programme: Research Grants