Sodium butyrate improves renal injury in diabetic nephropathy through AMPK/SIRT1/PGC-1α signaling pathway

Sci Rep. 2024 Aug 1;14(1):17867. doi: 10.1038/s41598-024-68227-8.

Abstract

Diabetic nephropathy (DN) is a prototypical chronic energy metabolism imbalance disease. The AMPK/Sirt1/PGC-1α signaling pathway plays a pivotal role in regulating energy metabolism throughout the body. Gut microbiota ferment indigestible carbohydrates to produce a variety of metabolites, particularly short-chain fatty acids (SCFAs), which exert positive effects on energy metabolism. However, the potential for SCFAs to ameliorate DN-associated renal injury via the AMPK/Sirt1/PGC-1α pathway remains a matter of debate. In this study, we investigated the effects of sodium butyrate (NaB), a SCFA, on energy metabolism in mice with spontaneous DN at two different doses. Body weight, blood glucose and lipid levels, urinary protein excretion, liver and kidney function, interleukin-6 (IL-6) levels, and the expressions of AMPK, phosphorylated AMPK (p-AMPK), mitofusin 2 (MFN2), optic atrophy 1 (OPA1), and glucagon-like peptide-1 receptor (GLP-1R) were monitored in mice. Additionally, butyrate levels, gut microbiota composition, and diversity in colonic stool were also assessed. Our findings demonstrate that exogenous NaB supplementation can improve hyperglycemia and albuminuria, reduce renal tissue inflammation, inhibit extracellular matrix accumulation and glomerular hypertrophy, and could alter the gut microbiota composition in DN. Furthermore, NaB was found to upregulate the expressions of MFN2, OPA1, p-AMPK, and GLP-1R in DN renal tissue. These results suggest that NaB could improve the composition of gut microbiota in DN, activate the AMPK/Sirt1/PGC-1α signaling pathway, and enhance mitochondrial function to regulate energy metabolism throughout the body. Collectively, our findings indicate that NaB may be a novel therapeutic agent for the treatment of DN.

Keywords: AMPK/Sirt1/PGC-1α signaling pathway; Diabetic nephropathy; Gut microbiota; Short-chain fatty acids; Sodium butyrate.

MeSH terms

  • AMP-Activated Protein Kinases* / metabolism
  • Animals
  • Butyric Acid* / pharmacology
  • Diabetic Nephropathies* / drug therapy
  • Diabetic Nephropathies* / metabolism
  • Diabetic Nephropathies* / pathology
  • Energy Metabolism / drug effects
  • Gastrointestinal Microbiome / drug effects
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha* / metabolism
  • Signal Transduction* / drug effects
  • Sirtuin 1* / metabolism

Substances

  • Sirtuin 1
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • AMP-Activated Protein Kinases
  • Butyric Acid
  • Ppargc1a protein, mouse
  • Sirt1 protein, mouse