Division of Kidney, Diabetes and Endocrine Diseases, Okayama University Hospital, Okayama, Japan.
Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Diabetes. 2024 May 1;73(5):763-779. doi: 10.2337/db23-0581.
The beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on kidney function are well-known; however, their molecular mechanisms are not fully understood. We focused on 78-kDa glucose-regulated protein (GRP78) and its interaction with SGLT2 and integrin-β1 beyond the chaperone property of GRP78. In streptozotocin (STZ)-induced diabetic mouse kidneys, GRP78, SGLT2, and integrin-β1 increased in the plasma membrane fraction, while they were suppressed by canagliflozin. The altered subcellular localization of GRP78/integrin-β1 in STZ mice promoted epithelial mesenchymal transition (EMT) and fibrosis, which were mitigated by canagliflozin. High-glucose conditions reduced intracellular GRP78, increased its secretion, and caused EMT-like changes in cultured HK2 cells, which were again inhibited by canagliflozin. Urinary GRP78 increased in STZ mice, and in vitro experiments with recombinant GRP78 suggested that inflammation spread to surrounding tubular cells and that canagliflozin reversed this effect. Under normal glucose culture, canagliflozin maintained sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA) activity, promoted ER robustness, reduced ER stress response impairment, and protected proximal tubular cells. In conclusion, canagliflozin restored subcellular localization of GRP78, SGLT2, and integrin-β1 and inhibited EMT and fibrosis in DKD. In nondiabetic chronic kidney disease, canagliflozin promoted ER robustness by maintaining SERCA activity and preventing ER stress response failure, and it contributed to tubular protection.
钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂对肾功能的有益影响是众所周知的；然而，其分子机制尚不完全清楚。我们专注于 78kDa 葡萄糖调节蛋白（GRP78）及其与 SGLT2 和整合素-β1 的相互作用，超出了 GRP78 的伴侣性质。在链脲佐菌素（STZ）诱导的糖尿病小鼠肾脏中，GRP78、SGLT2 和整合素-β1 在质膜部分增加，而在给予卡格列净时则受到抑制。STZ 小鼠中 GRP78/整合素-β1 的改变亚细胞定位促进了上皮间质转化（EMT）和纤维化，而卡格列净则减轻了这种变化。高葡萄糖条件下降低了细胞内 GRP78，增加了其分泌，并导致培养的 HK2 细胞发生 EMT 样变化，而卡格列净再次抑制了这种变化。STZ 小鼠的尿 GRP78 增加，而用重组 GRP78 进行的体外实验表明，炎症扩散到周围的管状细胞，而卡格列净逆转了这种作用。在正常葡萄糖培养下，卡格列净维持肌浆/内质网（ER）Ca2+-ATP 酶（SERCA）活性，增强 ER 稳健性，减少 ER 应激反应损伤，并保护近端肾小管细胞。总之，卡格列净恢复了 DKD 中 GRP78、SGLT2 和整合素-β1 的亚细胞定位，并抑制了 EMT 和纤维化。在非糖尿病慢性肾脏病中，卡格列净通过维持 SERCA 活性和防止 ER 应激反应失败来增强 ER 稳健性，并有助于肾小管保护。
