Fibroblasts in acute and chronic kidney injury

• Applicant: Professor Dr. Michael Zeisberg
• Subject Area: Nephrology
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 233914712

In the kidney, fibroblasts are well-established as principal mediators of pathological fibrogenesis. In contrast, insights into the physiological function of renal fibroblasts are almost non-existent. Here we ask the question, if fibroblasts have a physiological function in repair of acute kidney injury; and, if that is so, how this physiological role relates to their established detrimental function in pathological fibrogenesis. By demonstrating that ablation of fibroblasts in transgenic mice causes impaired regeneration of the tubular epithelium upon ischemia-reperfusion injury, we for the first time provide evidence for a physiological, beneficial role of fibroblasts in kidney repair. Because fibroblasts do not incorporate into the tubular epithelium, we hypothesized that fibroblasts aid kidney repair by paracrine stimulation of tubular regeneration. By performing transcriptome-analysis in FASC-sorted fibroblasts from post-ischemic mouse kidneys we identified the growth factor FGF4 to be selectively up-regulated in physiological repair of acute kidney injury. Based on these preliminary studies we hypothesize that fibroblasts aid the repair of acute kidney injury by secreting FGF4. Studies proposed in this application will elucidate the contribution of FGF4 to physiological repair of acute kidney injury using conditional knockout mice (specific aim 1) and explore molecular mechanisms that control FGF4 expression in kidney fibroblasts in the context of acute kidney injury (specific aim 2). In addition, our preliminary studies demonstrate, that the fibroblast activation, which is associated with pathological fibrogenesis is not associated with increased FGF4 expression, in striking contrast to physiological kidney regeneration. Based on this observation we hypothesize that absence of FGF4 contributes to the failure of the tubular epithelium to regenerate, a hallmark of chronic kidney disease. We further hypothesize, that fibroblasts in renal fibrogenesis undergo epigenetic modifications, and that failure to secrete FGF4 is one consequence of the underlying epigenetics. Studies proposed in aim 3 of the application will elucidate epigenetic mechanisms which prevent fibrotic fibroblasts from up-regulating FGF4 expression, and how this contributes to renal fibrogenesis. In summary, studies proposed in this application will for the first time establish mechanistic evidence for a specific physiological function of fibroblasts in kidney regeneration. Furthermore, studies will for the first time provide mechanistic insights, how epigenetics impact fibroblast behavior and how this may serve as link between acute kidney injury and chronic progressive kidney disease. Finally, FGF4 is a previously unsung molecule in the kidney and may have diagnostic and therapeutic utility in the future.

• DFG Programme: Research Grants