SGLT2 inhibition and acute kidney injury

SGLT2抑制剂是一类很有前途的新型药物，可以显著提高糖尿病和心力衰竭患者的心血管死亡率，并延缓慢性肾脏疾病的进展。尽管有这些好处，SGLT2抑制剂也会引起几种副作用，包括增加急性肾功能衰竭的频率，目前人们对此知之甚少。分析转录和代谢的变化，我们观察到，SGLT2抑制改变了超过50%的尿液中测得的661种代谢物。然而，短期和长期治疗之间有一个重要的区别。在小鼠的缺血模型中，短期的依帕格列酮治疗增加了肾缺血/再灌注损伤和急性心肌梗死后肾功能衰竭的风险，而长期的药物暴露并没有影响结果。因此，我们推测，短期的SGLT2抑制使肾脏容易受到低灌注和缺血的影响，而长期治疗激活了代偿信号级联反应，从而防止肾功能衰竭。因此，利用斑马鱼和小鼠模型，结合广泛的遗传和代谢特征，我们建议1)确定短期SGLT2抑制后增加缺氧敏感性的机制，2)提取长期SGLT2抑制后保护缺血的信号通路，3)利用这些信息来靶向急性肾脏损伤。

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.