GW1929 (an agonist of PPARγ) inhibits excessive production of reactive oxygen species in cisplatin-stimulated renal tubular epithelial cells, hampers cell apoptosis, and ameliorates renal injury.

Abstract

Cisplatin-induced nephrotoxicity has long been explored for development of preventative and therapeutic drugs. The current investigation focused on the renal protective effect of GW1929, an agonist for peroxisome proliferator-activated receptors gamma (PPARγ), on cisplatin-induced kidney injury. HK2 cells treated with 20 μM cisplatin and C57BL/6 mice injected with 20 mg/kg cisplatin were used as the cell model and animal model for acute kidney injury. HK2 cell viability after cisplatin or GW1929 (0-80 μM) treatment was tested using methyl thiazolyl tetrazolium assays. Flow cytometry analysis and TUNEL assays were used to measure cell apoptosis. Intracellular reactive oxygen species (ROS) level was measured through fluorescence intensities. Levels of blood urea nitrogen (BUN) and serum creatinine (SCr) were measured to evaluate the renal function of mice. For renal morphology observation and cell apoptosis assessment in vivo, hematoxylin-eosin staining and TUNEL assays were conducted. The concentrations of oxidative stress markers in renal samples were measured using colorimetric tests. It was found that GW1929 dose-dependently enhanced protein levels of PPARγ, PGC-1α and TFEB in HK2 cells. Meanwhile, intracellular ROS overproduction, the decrease in cell viability and excessive cell apoptosis mediated by cisplatin were reversed by GW1929. For in vivo experiments, GW1929 notably attenuated cisplatin-stimulated nephrotoxicity and oxidative stress while reducing BUN and Scr levels in cisplatin-challenged model mice. Moreover, GW1929 significantly dampened renal cell apoptosis in vivo. GW1929 mitigates renal tubular epithelial cell injury and renal damage by inhibiting oxidative stress and renal cell apoptosis.