ER stress modulated Klotho restoration: A prophylactic therapeutic strategy against acute kidney injury-diabetes comorbidity

Klotho is a renoprotective factor that is at the forefront of research as a potential therapeutic agent and biomarker of acute kidney injury (AKI). Endoplasmic reticulum (ER) stress and Klotho downregulation are the critical hallmarks of AKI progression. Importantly, the crosstalk between ER and Klotho is still elusive in AKI under diabetic condition. Therefore, this study aimed to elucidate the affiliation between ER stress and Klotho regulation by using the ischemia-reperfusion renal injury (IRI) model based on male Wistar rats and the hypoxia-reperfusion injury (HRI) using NRK52E cells. Study outcomes demonstrated that the expression of AKI biomarkers: plasma creatinine, neutrophil gelatinase-associated lipocalin, kidney-injury molecule 1, and ER stress markers such as binding immunoglobulin binding protein (BiP), R/PKR-like ER kinase (PERK), and eukaryotic initiation factor-2 (eIF2α), were observed during AKI. Increased ER stress was associated with apoptosis induction as depicted by increased levels of Poly (ADP-ribose) polymerase (PARP) and caspase-7 and decreased tubular Klotho expression. Under diabetic settings, ER stress and apoptosis were exacerbated by additional Klotho downregulation. Treatment with Tauroursodeoxycholic acid (TUDCA) inhibited the ER stress, apoptosis, restored endogenous Klotho levels and ameliorated AKI under diabetic and non-diabetic conditions. ER stress and Klotho appear to be shared factors involved in the pathogenesis of AKI-diabetes comorbidity and targeting them could prove a novel therapeutic approach.