Lee Hak Joo, Sun Yuyang, Das Falguni, Ju Wenjun, Nair Viji, Kevil Christopher G, Varadarajan Shankara, Zhang Guanshi, Ghosh Choudhury Goutam, Singh Brij B, Kretzler Matthias, Nelson Robert G, Sharma Kumar, Kasinath Balakuntalam S
Center for Precision Medicine, Department of Medicine, and.
Department of Periodontics, University of Texas Health, San Antonio, San Antonio, Texas, USA.
JCI Insight. 2025 Jan 9;10(1):e174848. doi: 10.1172/jci.insight.174848.
The role played by anionic channels in diabetic kidney disease (DKD) is not known. Chloride channel accessory 1 (CLCA1) facilitates the activity of TMEM16A (Anoctamin-1), a Ca2+-dependent Cl- channel. We examined if CLCA1/TMEM16A had a role in DKD. In mice with type 2 diabetes, renal cortical CLCA1 and TMEM16A content was increased. CLCA1 and TMEM16A content was associated with hydrogen sulfide (H2S) deficiency, mTOR complex 1 (mTORC1) activation, albuminuria, and matrix increase. Administering sodium hydrosulfide (NaHS), a source of H2S, mitigated these changes. In proximal tubular epithelial (MCT) cells, high glucose rapidly increased CLCA1 by recruiting the IL-6/STAT3 axis and augmented TMEM16A expression by stimulating its mRNA translation; these changes were abolished by NaHS. Patch clamp experiments showed that high glucose increased Cl- current in MCT cells that was ameliorated by NaHS and a TMEM16A chemical inhibitor. siRNA against CLCA1 or TMEM16A and TMEM16A inhibitor abolished high glucose-induced mTORC1 activation and matrix protein increase. Tubular expression of TMEM16A correlated with albuminuria in kidney biopsies from people with type 2 diabetes. We report a pathway for DKD in which H2S deficiency results in kidney injury by the recruitment of the CLCA1/TMEM16A/Cl- current system.
阴离子通道在糖尿病肾病（DKD）中所起的作用尚不清楚。氯离子通道辅助蛋白1（CLCA1）可促进TMEM16A（anoctamin-1，一种钙依赖性氯离子通道）的活性。我们研究了CLCA1/TMEM16A是否在DKD中发挥作用。在2型糖尿病小鼠中，肾皮质CLCA1和TMEM16A的含量增加。CLCA1和TMEM16A的含量与硫化氢（H2S）缺乏、mTOR复合物1（mTORC1）激活、蛋白尿和基质增加有关。给予硫化氢来源的硫氢化钠（NaHS）可减轻这些变化。在近端肾小管上皮（MCT）细胞中，高糖通过募集IL-6/STAT3轴迅速增加CLCA1，并通过刺激其mRNA翻译增加TMEM16A的表达；这些变化可被NaHS消除。膜片钳实验表明，高糖增加了MCT细胞中的氯离子电流，而NaHS和一种TMEM16A化学抑制剂可改善这种情况。针对CLCA1或TMEM16A的小干扰RNA以及TMEM16A抑制剂消除了高糖诱导的mTORC1激活和基质蛋白增加。在2型糖尿病患者的肾活检中，TMEM16A的肾小管表达与蛋白尿相关。我们报道了一条DKD的发病途径，即H2S缺乏通过募集CLCA1/TMEM16A/氯离子电流系统导致肾损伤。
