Early and Transient Activation of Fibroblast Promotes Tubule Repair after Acute Kidney Injury.

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PROJECT SUMMARY/ABSTRACT Career Development Plan My primary career goal is to become a successful, independent investigator and leader in the field of kidney disease. To achieve my career goal, I have assembled an advisory committee from a multi-disciplinary group of established researchers at the University of Pittsburgh (Pitt). These researchers are experts in the fields of bioinformatics, pathology, cell biology, immunology, and nephrology. My career development plan includes personal mentoring, focused coursework, practical research experience, and professional training. Pitt is one of the nation’s most distinguished, comprehensive universities and a major center of biomedical research national wide. It is committed to fostering the careers of research faculty and maintains a strong and well- established health sciences research program. All these factors establish a positive environment in my career development towards independence. Research Plan Acute kidney injury (AKI) is an abrupt or rapid decline in renal filtration that happens within a few hours or a few days. Most of the work in the field focuses on renal tubule damage, but research on repair of the tubules and what process promotes surviving tubular epitheliums to dedifferentiate is lacking. Cellular events involved in the early phases of AKI and the triggers or sources responsible for tubule dedifferentiation remain unclear. As the cell neighbor to renal tubules, we believe activated fibroblasts play a main role in inducing renal tubule repair after AKI. Our recent preliminary studies show that multiple fibroblast phenotypes were activated as early as 1 hour and reach peak at 12 hours after AKI, which is far earlier than tubular epithelium proliferation. We previously recognized that in chronic kidney disease (CKD), a tubule-derived novel growth factor, Sonic Hedgehog (Shh), specifically targets interstitial fibroblast, driving renal fibrosis through epithelial-mesenchymal communication (EMC). In our AKI mouse model, Shh was also directly secreted by renal tubules and was upregulated as early as 1 hour in injured kidneys. To our surprise, compared to its role in CKD, Shh plays a completely opposite role in AKI; it has a protective effect in AKI. Pharmacological inhibition of Shh suppressed fibroblast activity and aggravated AKI. In cultured fibroblasts, Shh causes transient fibroblast activation and secretion of hepatocyte growth factor (HGF), which we reported to have a renoprotective role in AKI. Therefore, our central hypothesis is that renal tubule-derived Shh induces early and transient fibroblast activation to promote AKI repair through a Shh-HGF feedback loop. We will test this hypothesis in two specific aims: 1) Determine the mechanism of Shh-mediated EMC in promoting renal repair after AKI. 2) Determine the roles of the Shh-HGF feedback loop in renal repair after AKI. Fully understanding the early stages of AKI pathogenesis will be very beneficial in determining AKI prognosis and designing novel future therapeutic strategies.