HDAC6 Inhibition with CAY10603 Alleviates Renal Fibrosis Against Pyroptosis in Tubular Injury

Background: The essential role of tubular damage has been highlighted during the progression of chronic kidney diseases (CKD), included diabetic nephropathy (DN), but the treatment options are still limited. Methods: We interrogated the connectivity Map (CMap) with tubular transcriptomic profiles of biopsy-proven DN to identify a drug to reverse the regulated genes in tubulointerstitial component of DN. The effects of potential drug were validated in vivo STZ-induced early and late stage diabetic CD-1 male mice, as well as in non-diabetic mice including adenine-induced CKD and LPS-induced septic kidney injury. Results: CAY10603, a specific inhibitor of histone deacetylase 6 (HDAC6), was identified as a drug to reverse the signature in both early- and late-stage DN. In patients with DN and mice with DKD, renal tubular expression of HDAC6 was significantly upregulated. In vivo, 5mg/kg dosage of CAY10603 significantly ameliorated tubular injury and tubulointerstitial fibrosis, reduced tubulointerstitial α-SMA and collagen I expression, and infiltration of F4/80+ macrophages in both early and late stage of diabetic kidney disease. In addition, CAY10603 also conferred renoprotection in non-diabetic mice including adenine-induced CKD and LPS-induced septic kidney injury. Mechanically, in vitro HK-2 cells, HDAC6 inhibition with CAY10603 regulated NLRP3 activation and membrane repair upstream and downstream of GSDMD. Conclusions: Collectively, CAY10603 exhibited therapeutic potential against pyroptosis in tubular injury of CKD Funding: Government Support - Non-U.S.