PP2Cm Dysregulation Is Associated with Impaired BCAA Catabolism and cGAS-STING Activation in Diabetic Kidney Disease

ABSTRACT: Background and Aims:Branched-chain amino acids (BCAAs) are increasingly implicated in diabetic kidney disease (DKD), yet the role of protein phosphatase 2C mitochondrial (PP2Cm), encoded by PPM1K and regulating BCAA catabolism through the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, remains unclear. We aimed to characterize PP2Cm-associated BCAA metabolic alterations and their clinical relevance in DKD.Methods and Results: Integrated analyses of kidney transcriptomics, whole-blood RNA sequencing, and urinary metabolomics, followed by validation in 256 individuals with type 2 diabetes mellitus (T2DM) and DKD, revealed coordinated downregulation of PPM1K and BCKDHA, indicating suppression of BCAA catabolic pathways. Circulating BCAA levels displayed a stage-dependent pattern during DKD progression, with early elevation followed by reduction in advanced disease, [ Present/permanent address:The First Affiliated Hospital of Xinjiang Medical University No. 137 Liyushan South Road, Xinshi District, Urumqi 830054, Xinjiang Uygur Autonomous Region, P.R. China]whereas urinary BCAA-to-creatinine ratios increased progressively. Serum PP2Cm levels declined with DKD severity and were independently associated with estimated glomerular filtration rate (eGFR). In DKD mice, reduced renal PP2Cm expression was accompanied by increased inhibitory BCKDHA phosphorylation and activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Conclusions: DKD is characterized by disruption of PP2Cm-associated BCAA metabolic regulation involving both transcriptional and post-translational mechanisms. The association between altered BCAA metabolism and cGAS-STING activation provides insights into metabolic–inflammatory interactions in DKD. Serum PP2Cm and urinary BCAA-to-creatinine ratios may represent candidate biomarkers of DKD-associated metabolic alterations.

INSTRUMENT(S): Liquid Chromatography MS - alternating - hilic

PROVIDER: MTBLS15967 | MetaboLights | 2026-10-09

REPOSITORIES: MetaboLights