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钠-葡萄糖协同转运蛋白 2 抑制剂达格列净可改善高尿酸血症肾病的肾纤维化。

The SGLT2 inhibitor dapagliflozin ameliorates renal fibrosis in hyperuricemic nephropathy.

机构信息

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.

Division of Nephrology, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, No. 158 Wuyang Avenue, Enshi, China.

出版信息

Cell Rep Med. 2024 Aug 20;5(8):101690. doi: 10.1016/j.xcrm.2024.101690.

DOI:10.1016/j.xcrm.2024.101690
PMID:39168099
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11384938/
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.

摘要

高尿酸血症肾病（HN）是一种全球性的代谢紊乱疾病，其特征为尿酸（UA）代谢功能障碍，导致高尿酸血症（HUA）和肾小管间质纤维化（TIF）。钠依赖性葡萄糖转运蛋白 2 抑制剂达格列净已被证明在降低慢性肾脏病（CKD）患者的血清 UA 水平方面具有潜力，但它对 HN 的保护作用仍不确定。本研究通过对患者、HN 小鼠和 UA 刺激的 HK-2 细胞进行组织学、生化和转录组学分析，研究了 HN 中的功能、病理和分子变化。研究结果表明，UA 诱导的肾小管功能障碍和纤维化激活，达格列净可显著减轻这些变化。转录组学分析确定了雌激素相关受体 α（ERRα），这是 HN 中下调的转录因子。ERRα 敲入小鼠和 ERRα 过表达的 HK-2 细胞表现出对 UA 的抗性，而 ERRα 抑制则加剧了 UA 的作用。达格列净靶向 ERRα，激活 ERRα-有机阴离子转运蛋白 1（OAT1）轴，以增强 UA 排泄并减少 TIF。此外，达格列净改善了非 HN CKD 模型中的肾纤维化，突出了 ERRα-OAT1 轴在 HN 和 CKD 中的治疗意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfaf/11384938/83cd67c04a55/gr7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfaf/11384938/daa1e6ab895f/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfaf/11384938/860da6366fb5/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfaf/11384938/4d0c3889f20e/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfaf/11384938/aad877e761fb/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfaf/11384938/a6e5dd411e3e/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfaf/11384938/f6dd13f23ec6/gr5.jpg
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