Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS

Abstract

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. TGF-b1/Smad3 signalling plays a major pathological role in DN; however, the contribution of Smad4 has not been examined. Smad4 depletion in the kidney using anti-Smad4 locked nucleic acid halted progressive podocyte damage and glomerulosclerosis in mouse type 2 DN, suggesting a pathogenic role of Smad4 in podocytes. Smad4 is upregulated in human and mouse podocytes during DN. Conditional Smad4 deletion in podocytes protects mice from type 2 DN, independent of obesity. Mechanistically, hyperglycaemia induces Smad4 localization to mitochondria in podocytes, resulting in reduced glycolysis and oxidative phosphorylation and increased production of reactive oxygen species. This operates, in part, via direct binding of Smad4 to the glycolytic enzyme PKM2 and reducing the active tetrameric form of PKM2. In addition, Smad4 interacts with ATPIF1, causing a reduction in ATPIF1 degradation. In conclusion, we have discovered a mitochondrial mechanism by which Smad4 causes diabetic podocyte injury.

Deciphering the genomic and lncRNA landscapes of aerobic glycolysis identifies potential therapeutic targets in pancreatic cancer

“…Interestingly, IDO1 plays important roles in maintaining the pluripotency of primed human embryonic stem cells by upregulating glycolysis. Moreover, SMAD4 promotes diabetic nephropathy by reducing glycolysis via direct interaction with PKM2 30 . However, whether aerobic glycolysis is regulated by these CNVs in PDAC warrants further investigation.…”

Mitochondrial Redox Signaling and Oxidative Stress in Kidney Diseases

“…TGFβ1 and NF-κB are also localized in mitochondria, regulating mitochondrial proteins [98]. Moreover, the mitochondrial localization of both proteins might indicate that inflammation and fibrosis processes are regulated by mtROS production.…”

CFAP45 is a Potential Predictor of Mitochondrial Dysfunction in Diabetic Kidney Disease

“…According to previous studies, hyperglycemia induces Smad4 localization to mitochondria can induce diabetic nephropathy by reducing glycolysis and oxidative phosphorylation (OXPHOS). 26 Furthermore, stimulation of AMP-activated protein kinase (AMPK) has been shown to possess a powerful ability to inhibit the nuclear translocation of Smad4 in diabetic kidneys. 27 In addition, drugs that could re-establish the homeostasis of mitochondrial energy are promising drugs for the restoration of DKD, including orally active synthetic adiponectin receptor agonist 28 , berberine 29 and mitochondria-targeted antioxidant MitoQ 30 .…”