Empagliflozin protects the kidney by reducing toxic ALB (albumin) exposure and preventing autophagic stagnation in proximal tubules
Abstract
ABSTRACT The renoprotective effects of SLC5A2/SGLT2 (solute carrier 5 (sodium/glucose cotransporter), member 2) inhibitors have recently been demonstrated in non-diabetic chronic kidney disease (CKD), even without overt albuminuria. However, the mechanism underlying this renoprotection is largely unclear. We investigated the renoprotective mechanisms of the SLC5A2 inhibitor empagliflozin with a focus on ALB (albumin) reabsorption and macroautophagy/autophagy in proximal tubules using wild-type or drug-inducible lrp2/Megalin or atg5 knockout mice with high-fat diet (HFD)-induced obesity or 5/6 nephrectomy that elevated intraglomerular pressure without overt albuminuria. Empagliflozin treatment of HFD-fed mice reduced several hallmarks of lipotoxicity in the proximal tubules, such as phospholipid accumulation in the lysosome, inflammation and fibrosis. Empagliflozin, which decreases intraglomerular pressure, not only reduced the HFD-induced increase in ALB reabsorption via LRP2 in the proximal tubules (i.e. total nephron ALB filtration), as assessed by urinary ALB excretion caused by genetic ablation of Lrp2, but also ameliorated the HFD-induced imbalance in circulating ALB-bound fatty acids. Empagliflozin alleviated the HFD-induced increase in autophagic demand and successfully prevented autophagic stagnation in the proximal tubules. Similarly, empagliflozin decreased ALB exposure and autophagic demand in 5/6 nephrectomized mice. Finally, empagliflozin reduced HFD-induced…
Read the paper
Related studies
- Strategy for Mitigating DKA Risk in Patients with Type 1 Diabetes on Adjunctive Treatment with SGLT Inhibitors: A STICH Protocol
- Glucoraphanin: a broccoli sprout extract that ameliorates obesity-induced inflammation and insulin resistance
- SGLT2 Inhibitors in Heart Failure: Targeted Metabolomics and Energetic Metabolism
- Mechanisms of blood pressure reduction with sodium-glucose co-transporter 2 (SGLT2) inhibitors
- Sodium-glucose cotransporter inhibitors: beyond glycaemic control
- Decoding the effects of SGLT2 inhibitors on cardiac arrhythmias in heart failure
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.