ECEESPE2025 Poster Presentations Diabetes and Insulin (143 abstracts)
1The Affiliated Hospital of Southwest Medical University, Department of Endocrinology and Metabolism, Luzhou, China; 2Macau University of Science and Technology, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau, China; 3The Affiliated Hospital of Southwest Medical University, Department of Pathology, Luzhou, China
JOINT547
Objective: Diabetic kidney disease (DKD) has a complex pathogenesis, and current therapies offer limited benefits. Gut-derived metabolites, particularly indole-3-propanoic acid (IPA), a deaminated derivative of tryptophan produced by gut bacteria, may play a role in DKD. This study aimed to assess serum metabolic alterations in DKD and explore the effects of IPA on glomerular endothelial cells (GECs) and mitochondrial function.
Methods: Untargeted metabolomics was employed to identify differentially expressed metabolites in DKD mouse serum, followed by validation in DKD patients using UHPLC-MRM-MS/MS. IPA supplementation was tested in high-fat diet combined with STZ-induced DKD mice to evaluate its effects on kidney morphology, glomerular filtration barrier integrity, fibrosis, and albuminuria. In vitro, high glucose-stimulated GECs were used to investigate IPAs impact on mitochondrial function, the PGC-1α pathway, and SIRT1 protein degradation.
Results: Metabolomics revealed significant alterations in tryptophan metabolism and its metabolites, including IPA. UHPLC-MRM-MS/MS analysis confirmed reduced IPA levels in DKD patients, which were negatively correlated with fasting blood glucose, HbA1c, and UACR, and positively correlated with eGFR. In DKD mice, IPA supplementation improved kidney structure, reduced fibrosis, enhanced glomerular filtration barrier integrity, and decreased UACR. IPA also alleviated mitochondrial abnormalities in GECs, increasing mitochondrial quantity and ATP, while reducing oxidative stress markers such as malondialdehyde (MDA). In vitro, IPA reduced ROS and MDA in GECs, improved mitochondrial membrane potential and ATP levels, and upregulated mtTFA and SOD2 expression. Additionally, IPA inhibited SIRT1 degradation via the ubiquitin-proteasome pathway, leading to increased SIRT1 levels and activation of the SIRT1/PGC-1α pathway, which enhanced mitochondrial biogenesis and antioxidant defense.
Conclusions: IPA, a gut-derived metabolite, is reduced in DKD and correlates with UACR. IPA supplementation alleviates albuminuria in DKD by improving mitochondrial function, reducing oxidative stress, and activating the SIRT1/PGC-1α signaling pathway. These findings suggest that IPA is a potential therapeutic target for DKD, offering new insights into renal protection through enhanced mitochondrial biogenesis and antioxidant capacity.