Endothelial SIRT3 regulates myofibroblast metabolic shifts in diabetic kidneys

Abstract

Summary Defects in endothelial cells cause deterioration in kidney function and structure. Here, we found that endothelial SIRT3 regulates metabolic reprogramming and fibrogenesis in the kidneys of diabetic mice. By analyzing, gain of function of the SIRT3 gene by overexpression in a fibrotic mouse strain conferred disease resistance against diabetic kidney fibrosis, whereas its loss of function in endothelial cells exacerbated the levels of diabetic kidney fibrosis. Regulation of endothelial cell SIRT3 on fibrogenic processes was due to tight control over the defective central metabolism and linked activation of endothelial-to-mesenchymal transition (EndMT). SIRT3 deficiency in endothelial cells stimulated the TGFβ/Smad3-dependent mesenchymal transformations in renal tubular epithelial cells. These data demonstrate that SIRT3 regulates defective metabolism and EndMT-mediated activation of the fibrogenic pathways in the diabetic kidneys. Together, our findings show that endothelial SIRT3 is a fundamental regulator of defective metabolism regulating health and disease processes in the kidney.

Fibrosis: Sirtuins at the checkpoints of myofibroblast differentiation and profibrotic activity

“…41 Studies on diabetic mice showed that loss of Sirt3 favoured the EMT of renal tubular epithelial cells through the TGF-β/Smad3 axis, and exacerbated kidney fibrosis. 42 Accordingly, Sirt3 expression protects the liver, heart and kidney from the development of fibrosis, as demonstrated in humans and animal models. 158 In particular, studies performed both in vitro and in a mouse model of renal fibrosis demonstrated that up-regulation of Sirt3 activity resulted in a reduced fibrotic response, through regulation of mitochondrial dynamics and the NF-kB/TGF-β1/Smad signalling pathway.…”

“…37,38 Sirt3 dampens the canonical TGF-β signalling pathway, also due to the deacetylation of Smad3, thus reducing the cellular profibrotic responses. 40,42,43,93 Sirt4 can exert antifibrotic activity by deacetylating Smad4. 47 Interestingly, Sirt6 has interacting partners belonging to both the canonical and non-canonical TGF-β signalling pathways, and its effects are antifibrotic.…”

Coronavirus Disease (COVID)-19 and Diabetic Kidney Disease

“…In our laboratory, we have investigated crucial molecules that provide endothelial cell stability integrity, such as endothelial SIRT3, which is an essential mitochondrial protein and maintains the balance of fuel preference between healthy and damaged endothelial cells in diabetes [ 39 , 146 , 147 ]. Another study demonstrates that endothelial FGFR1 signaling is also important for endothelial cell heath in diabetic kidneys and the heart [ 148 , 149 ].…”

Interactions among Long Non-Coding RNAs and microRNAs Influence Disease Phenotype in Diabetes and Diabetic Kidney Disease

“…Pathological stimuli such as inflammation, diabetes and ageing influence EndMT events in the kidneys [ 69 ]. Endothelial SIRT3, the nuclear receptor glucocorticoid receptor (GR) and cell surface FGFR1 are critical regulators of TGFβ signaling and EndMT in diabetic kidneys [ 70 , 71 , 72 , 73 ]. The kidneys of diabetic mice showed both progressive glomerular sclerosis and tubulointerstitial fibrosis, which was associated with approximately 40% of all FSP-1-positive cells and 50% of αSMA-positive stromal cells were CD31-positive [ 74 ].…”