Sodium-glucose co-transporter-2 inhibitors (SGLT2i)为心肾保护提供了支持，但分子机制仍不完全清楚。我们探究SGLT2i对Klotho的影响，Klotho是一种具有抗衰老、肾保护和心脏保护特性的肾源性蛋白质。一项真实世界的前瞻性观察研究评估了在早期糖尿病性肾病（DKD）患者中使用SGLT2i（canagliflozin、dapagliflozin、empagliflozin）或二肽肽酶-4抑制剂（DPP4i）的影响。测量了血清和尿液可溶性Klotho、蛋白尿和血清和尿液肿瘤坏死因子-α（TNFa）。在体外研究中，探究了SGLT2i对肾近曲小管细胞的Klotho mRNA和蛋白质的影响，这些细胞暴露于高葡萄糖浓度以模拟糖尿病环境，暴露于蛋白尿以模拟蛋白尿，以及暴露于炎症细胞因子TWEAK以模拟DKD的炎症环境。基线尿液Klotho与蛋白尿（r - 0.45，P < 0.001）和尿液TNFa（r - 0.40，P < 0.01）呈负相关。DPP4i和SGLT2i的HbA1c下降幅度相似，但只有SGLT2i降低了eGFR、蛋白尿和尿液TNFa并增加（P < 0.001）血清（5.2 %）和尿液Klotho（38.9 %）。尿液TNFa的变化（β - 0.53，P = 0.001）和蛋白尿的变化（β - 0.31，P < 0.05）与尿液Klotho的变化独立相关（调整后R2 = 0.54，P < 0.001）。肾小管细胞的研究表明，高葡萄糖、蛋白尿和TWEAK降低了Klotho mRNA表达和蛋白质水平，而这种效应同样被SGLT2i防止。SGLT2i增加了2型糖尿病患者以及早期DKD患者中Klotho的可用性，以及应激状态下的小管细胞中的Klotho。这种对Klotho的影响有助于SGLT2i提供的肾脏和心脏保护作用。版权所有©2022年作者。由Elsevier Masson SAS出版。保留所有权利。

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) provide cardiorenal protection. However, the molecular mechanisms remain poorly understood. We explored the impact of SGLT2i on Klotho, a kidney-derived protein with antiaging, renal-protective and heart-protective properties. A real world prospective observational study addressed the impact of initiating SGLT2i (canagliflozin, dapagliflozin, empagliflozin) or dipeptidyl peptidase-4 inhibitors (DPP4i) in patients with early diabetic kidney disease (DKD). Serum and urinary soluble Klotho, albuminuria and serum and urinary tumor necrosis factor-alpha (TNFa) were measured. The effect of SGLT2i on Klotho mRNA and protein was explored in vitro in kidney proximal tubular cells stressed with high glucose concentrations to simulate the diabetic milieu, albumin to simulate albuminuria, and the inflammatory cytokine TWEAK to simulate the inflammatory environment in DKD. Baseline urinary Klotho was negatively associated with albuminuria (r - 0.45, P < 0.001) and urinary TNFa (r - 0.40, P < 0.01). Both DPP4i and SGLT2i reduced HbA1c similarly, but only SGLT2i decreased eGFR, albuminuria and urinary TNFa and increased (P < 0.001) serum (5.2 %) and urinary Klotho (38.9 %). Changes in urinary TNFa (β - 0.53, P = 0.001) and albuminuria (β - 0.31, P < 0.05) were independently associated with changes in urinary Klotho (adjusted R2 = 0.54, P < 0.001). Studies in renal tubular cells demonstrated that high glucose, albumin and TWEAK decreased Klotho mRNA expression and protein levels, an effect similarly prevented by SGLT2i. SGLT2i increase Klotho availability in type 2 diabetic patients with poorly controlled diabetes and early DKD, as well as in stressed tubular cells. This effect on Klotho may contribute to the kidney and heart protection afforded by SGLT2i.Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.