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Kidney Week

Abstract: PO0671

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

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Hou, Qing, National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing, China, Nanjing, Jiangsu, China
  • Shuyan, Kan, National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing, China, Nanjing, Jiangsu, China
  • Jiang, Song, National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing, China, Nanjing, Jiangsu, China
  • Liu, Zhihong, National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing, China, Nanjing, Jiangsu, China
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.

Conclusion

Collectively, CAY10603 exhibited therapeutic potential against pyroptosis in tubular injury of CKD

Funding

  • Government Support – Non-U.S.