Save Kidneys in Cisplatin Chemotherapy by blocking HDAC6

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Project Summary Cisplatin and its derivatives are the most widely used chemotherapeutic agents for treating solid tumors. However, cisplatin induces kidney injury during its use in cancer therapy. Currently, no treatment is available for cisplatin-induced acute and chronic kidney injury except supportive care. The goal of this project is to elucidate the role and mechanism of histone deacetylase 6 (HDAC6) in cisplatin-induced kidney injury, fibrosis and chronic kidney disease (CKD), and to identify HDAC6 inhibition as a novel approach for renoprotection. Our preliminary studies show that HDAC6 is up-regulated in acute kidney injury (AKI) induced by a single high-dose of cisplatin in mice and pharmacological inhibition of HDAC6 attenuates renal tubular apoptosis and AKI in this model. HDAC6 is also highly induced by repeated low-dose cisplatin treatment, which is accompanied by renal interstitial fibrosis, persistent activation of epidermal growth factor receptor (EGFR) and autophagy, and deacetylation of α-tubulin, a key process in cilium disassembly. Moreover, cisplatin treatment induces shortening of primary cilium in cultured renal epithelial cells, and the cells with shorter cilia are more sensitive to cisplatin-induced apoptosis. These studies provide preliminary evidence that HDAC6 may mediate cisplatin-induced kidney damage and that the underlying mechanism may involve EGFR, autophagy and ciliary disassembly. These data, together with a known cancer-promoting role of HDAC6 in tumors, have led to our hypothesis that blockade of HDAC6 may protect kidneys during cisplatin chemotherapy while enhancing its anti-cancer efficacy in tumors. Mechanistically, HDAC6 may contribute to cisplatin-induced kidney problems through the activation of EGFR and autophagy, and disassembly of primary cilium in renal tubular cells. To test these hypotheses, we will determine (1) whether blockade of HDAC6 can protect kidneys during cisplatin treatment while enhancing the chemotherapy effects in tumors; (2) whether HDAC6 contributes to cisplatin-induced renal injury, fibrosis and CKD by persistent activation of EGFR and autophagy; and (3) whether HDAC6-mediated ciliary disassembly aggravates kidney injury, fibrosis and CKD following cisplatin treatment. This multiple PI project takes advantage of the complementary expertise of Dr. Shougang Zhuang in EGFR signaling and epigenetic regulation and Dr. Zheng Dong in autophagy and cisplatin nephrotoxicity. Successful completion of the proposed studies will define the therapeutic effect of HDAC6 inhibition on cisplatin-induced renal damage and fibrosis, elucidate the underlying mechanisms, and identify a novel strategy for kidney protection while enhancing chemotherapeutic efficacy.