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  3. The SGLT2 inhibitor dapagliflozin ameliorates renal fibrosis in hyperuricemic nephropathy

The SGLT2 inhibitor dapagliflozin ameliorates renal fibrosis in hyperuricemic nephropathy

  • Cell Rep Med. 2024 Aug 20;5(8):101690. doi: 10.1016/j.xcrm.2024.101690.
Hongtu Hu 1,  Weiwei Li 2,  Yiqun Hao 3,  Zhuan Peng 3,  Zhengping Zou 4,  Jiali Wei 5,  Ying Zhou 6,  Wei Liang 7,  Yun Cao 8
Affiliations

Affiliations

  • 1 Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China; Key Clinical Research Center of Kidney Disease in Hubei, 238 Jiefang Road, Wuhan, China; Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.
  • 2 Division of Nephrology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, No. 158 Wuyang Avenue, Enshi, China.
  • 3 Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.
  • 4 Division of Nephrology, Qianjiang Hospital Affiliated to Renmin Hospital of Wuhan University, Wuhan, China; Qianjiang Clinical Medical College, Health Science Center, Yangtze University, Jingzhou, China.
  • 5 Department of Nephrology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, China.
  • 6 Department of Radiology and Nuclear Medicine, Xuanwu Hospital, Capital Medical University, No. 45 Changchun St, Xicheng District, Beijing 100053, China. Electronic address: zhouying2018@whu.edu.cn.
  • 7 Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China; Key Clinical Research Center of Kidney Disease in Hubei, 238 Jiefang Road, Wuhan, China. Electronic address: dr.liangwei@whu.edu.cn.
  • 8 Department of Nephrology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, China. Electronic address: yuncao1223@hainmc.edu.cn.
PMID: 39168099 DOI: 10.1016/j.xcrm.2024.101690
Abstract

Hyperuricemic nephropathy (HN) is a global metabolic disorder characterized by uric acid (UA) metabolism dysfunction, resulting in hyperuricemia (HUA) and tubulointerstitial fibrosis (TIF). Sodium-dependent glucose transporter 2 inhibitor, dapagliflozin, has shown potential in reducing serum UA levels in patients with chronic kidney disease (CKD), though its protective effects against HN remain uncertain. This study investigates the functional, pathological, and molecular changes in HN through histological, biochemical, and transcriptomic analyses in patients, HN mice, and UA-stimulated HK-2 cells. Findings indicate UA-induced tubular dysfunction and fibrotic activation, which dapagliflozin significantly mitigates. Transcriptomic analysis identifies estrogen-related receptor α (ERRα), a downregulated transcription factor in HN. ERRα knockin mice and ERRα-overexpressed HK-2 cells demonstrate UA resistance, while ERRα inhibition exacerbates UA effects. Dapagliflozin targets ERRα, activating the ERRα-organic anion transporter 1 (OAT1) axis to enhance UA excretion and reduce TIF. Furthermore, dapagliflozin ameliorates renal fibrosis in non-HN CKD models, underscoring the therapeutic significance of the ERRα-OAT1 axis in HN and CKD.

Keywords

ERRα; OAT1; dapagliflozin; hyperuricemic nephropathy; tubulointerstitial fibrosis.

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