GLDC alleviates cisplatin-induced apoptosis, cellular senescence, and production of reactive oxygen species via regulating UCP1 in the kidney

Abstract

Aims

Glycine decarboxylase (GLDC) is a mitochondrial enzyme that mediates the degradation of glycine as part of the glycine cleavage system. Although GLDC expression in the kidney is second highest next to the liver, very little is known as to the role of GLDC in the kidney. Thus, this study aimed to elucidate the role of GLDC in the kidney.

Materials and methods

HK-2 renal proximal tubular cells with GLDC overexpression and knockdown were established to investigate function of GLDC in cells treated with cisplatin (CP). For in vivo experiments, C57BL/6J mice were used in a CP-induced AKI model, with and without treatment with (aminooxy)acetic acid (AOAA), a GLDC inhibitor.

Key findings

We found that GLDC overexpression attenuated CP-induced apoptosis, cellular senescence and production of reactive oxygen species (ROS) in HK2 cells, while GLDC knockdown aggravated these effects. Moreover, GLDC overexpression stimulated proliferation of HK-2 cells, while GLDC knockdown attenuated cell growth. Mechanistically, we found that effects of GLDC are mediated via modulating mitochondrial uncoupling protein 1 (UCP1). GLDC overexpression increased UCP1, while GLDC knockdown decreased UCP1. Knockdown of UCP1 reversed GLDC-mediated attenuation of CP-induced cellular senescence and ROS production. Treatment of AOAA into acute kidney injury (AKI)-induced mice aggravated AKI injury, increasing biomarkers, fibrosis and senescence associated-β-galactosidase staining.

Significance

GLDC protects CP-induced apoptosis, cellular senescence, and ROS production in proximal tubular cells via a UCP-mediated pathway and lays a scientific foundation that could support a therapeutic strategy that targets GLDC for the treatment of cisplatin-induced AKI.