Chang Shiao-Ying, Liao Min-Chun, Miyata Kana N, Pang Yuchao, Zhao Xin-Ping, Peng Junzheng, Rivard Alain, Ingelfinger Julie R, Chan John S D, Zhang Shao-Ling
Department of Medicine, Université de Montréal, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), 900 Saint Denis Street, Montréal, QC H2 X 0A9, Canada.
Department of Medicine, Université de Montréal, Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), 900 Saint Denis Street, Montréal, QC H2 X 0A9, Canada; Division of Nephrology, Department of Internal Medicine, Saint Louis University, 1008 Spring Ave. St Louis, MO 63110, USA.
Transl Res. 2025 Mar;277:13-26. doi: 10.1016/j.trsl.2024.12.005. Epub 2025 Jan 3.
Renal hedgehog interacting protein (Hhip) activates sodium-glucose cotransporter 2 (Sglt2) expression and promotes tubular senescence in murine diabetic kidney disease (DKD), yet its underlying mechanism(s) are poorly understood. Here we study the effect of the SGLT2 inhibitor, canagliflozin on tubulopathy (fibrosis and apoptosis) in Akita/Hhip-transgenic (Tg) mice with overexpression of Hhip in their renal proximal tubular cells (RPTCs) and its relevant mechanisms. The DKD-tubulopathy with pronounced Sglt2 expression was aggravated in the kidney of Akita/Hhip-Tg cf. Akita/non-Tg mice. A strong association was observed between Hhip and tubular senescence in Nephroseq from the Nakagawa chronic kidney disease study. Both in vivo and in vitro, excessive Hhip in RPTCs triggered RPTC senescence (polyploidization and cytoskeleton destabilization) and released extracellular vesicles (EVs) carrying Hhip (EVs), most of which were apoptotic bodies (ABs) or microvesicles (MVs) and little exosomes (EXOs). Further, Hhip stimulated β2-microglobulin, which further interacts with EVs, together facilitating RPTC turn-over from cellular senescence to fibrosis and/or apoptosis, ultimately leading to advanced tubulopathy. In contrast, canagliflozin administration offset the action of Hhip in RPTCs, thereby preventing DKD progression. In conclusion, canagliflozin prevented excessive Hhip-mediated tubulopathy, possibly via the inhibition of excessive Hhip carried by extracellular vehicles in DKD.
肾刺猬相互作用蛋白（Hhip）可激活钠-葡萄糖协同转运蛋白2（Sglt2）的表达，并促进小鼠糖尿病肾病（DKD）中的肾小管衰老，但其潜在机制尚不清楚。在此，我们研究了SGLT2抑制剂卡格列净对肾近端小管细胞（RPTC）中Hhip过表达的秋田/Hhip转基因（Tg）小鼠肾小管病变（纤维化和凋亡）的影响及其相关机制。与秋田/非Tg小鼠相比，秋田/Hhip-Tg小鼠肾脏中具有明显Sglt2表达的DKD肾小管病变加重。在中川慢性肾病研究的Nephroseq中，观察到Hhip与肾小管衰老之间存在密切关联。在体内和体外，RPTC中过量的Hhip都会引发RPTC衰老（多倍体化和细胞骨架不稳定），并释放携带Hhip的细胞外囊泡（EVs），其中大部分是凋亡小体（ABs）或微囊泡（MVs），几乎没有外泌体（EXOs）。此外，Hhip刺激β2-微球蛋白，后者进一步与EVs相互作用，共同促进RPTC从细胞衰老向纤维化和/或凋亡转变，最终导致晚期肾小管病变。相比之下，给予卡格列净可抵消Hhip在RPTC中的作用，从而防止DKD进展。总之，卡格列净可能通过抑制DKD中细胞外载体携带的过量Hhip，预防了过量Hhip介导的肾小管病变。
