The SGLT2 inhibitor dapagliflozin ameliorates renal fibrosis in hyperuricemic nephropathy.

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2024-08-20 DOI:10.1016/j.xcrm.2024.101690

Hongtu Hu, Weiwei Li, Yiqun Hao, Zhuan Peng, Zhengping Zou, Jiali Wei, Ying Zhou, Wei Liang, Yun Cao

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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.

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SGLT2抑制剂达帕格列净可改善高尿酸血症肾病的肾脏纤维化。

高尿酸血症肾病（HN）是一种全球性代谢性疾病，其特点是尿酸（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体 2 抑制剂达帕格列净（dapagliflozin）在降低慢性肾脏病（CKD）患者血清 UA 水平方面具有潜力，但其对 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、生化和转录组分析，研究了 HN 的功能、病理和分子变化。研究结果表明，尿酸诱导肾小管功能障碍和纤维化活化，而达帕利洛嗪能显著缓解这种情况。转录组分析发现，雌激素相关受体α（ERRα）是HN中一个下调的转录因子。ERRα基因敲除小鼠和ERRα过表达的HK-2细胞表现出抗UA性，而抑制ERRα会加剧UA效应。达帕格列净靶向ERRα，激活ERRα-有机阴离子转运体1（OAT1）轴，从而促进尿酸排泄并降低TIF。此外，达帕格列净还能改善非 HN CKD 模型中的肾脏纤维化，这凸显了ERRα-OAT1 轴在 HN 和 CKD 中的治疗意义。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.

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