SGLT2 inhibition and acute kidney injury

• Applicant: Professor Dr. Gerd Walz
• Subject Area: Nephrology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 518086603

SGLT2 inhibitors are a promising new class of drugs that significantly improve cardiovascular mortality in patients with diabetes and heart failure, and delay the progression chronic kidney disease. Despite these benefits, SGLT2 inhibitors also cause several side effects including an increased frequency of acute kidney failure that are currently poorly understood. Analyzing the transcriptional and metabolomic changes, we observed that SGLT2 inhibition alters more than 50% of the 661 metabolites measured in the urine of mice treated with empagliflozin. However, there was an important difference between short- and long-term treatments. While short-term empagliflozin treatment increased the risk for renal failure after renal ischemia/reperfusion injury and after acute myocardial infarction, long-term drug exposure did not affect the outcome in mouse ischemia models. We therefore postulate that short-term SGLT2 inhibition renders kidneys susceptible to hypo-perfusion and ischemia, while prolonged treatment activates compensatory signaling cascades that prevent renal failure. Using zebrafish and mouse models in combination with extensive genetic and metabolic profiling, we propose therefore 1) to identify the mechanisms that increase the susceptibility to hypoxia after short-term SGLT2 inhibition, 2) to extract the signaling pathways that protect against ischemia after long-term SGLT2 inhibition, and 3) to use this information to target acute kidney injury.

• DFG Programme: Research Grants