Suppression of Endothelial-to-Mesenchymal Transition by SIRT (Sirtuin) 3 Alleviated the Development of Hypertensive Renal Injury

Abstract

Endothelial-to-mesenchymal transition (EndoMT) has recently emerged as a potentially important contributor in promoting fibrosis in chronic kidney disease. However, little is known about the role and molecular basis of its involvement in hypertensive renal injury. Here, we aim to determine the role of SIRT (sirtuin) 3 on EndoMT in hypertensive renal injury and to explore its underlying mechanisms. We found that SIRT3 expression was significantly reduced in Ang II (angiotensin II)-induced hypertensive model, accompanied with induction of EndoMT and increased reactive oxygen species and renal fibrosis. In SIRT3 (SIRT3 knockout) mice subjected to Ang II infusion, renal dysfunction was aggravated with an increased EndoMT and reactive oxygen species level, whereas in SIRT3-Tg (SIRT3 endothelial cell-specific transgenic) mice, the Ang II-induced renal fibrosis and EndoMT and oxidative stress were ameliorated. With primary mouse glomerular endothelial cells, we confirmed that Ang II treatment initiated EndoMT and decreased catalase expression, which were suppressed by SIRT3 overexpression. Using immunoprecipitation, luciferase, and chromatin immunoprecipitation assay, we demonstrated that SIRT3-mediated deacetylation and nuclear localization of Foxo3a (forkhead box O3a) resulted in activated Foxo3a-dependent catalase expression. Moreover, Foxo3a knockdown abolished SIRT3-mediated suppression of EndoMT. In conclusion, these results established the SIRT3-Foxo3a-catalase pathway as a critical factor in the maintenance of endothelial homeostasis and point to an important role of EndoMT in the vascular pathology of renal fibrosis, which may provide a new therapeutic target to impede the progression of hypertensive renal injury.

SIRT7 deficiency suppresses inflammation, induces EndoMT, and increases vascular permeability in primary pulmonary endothelial cells

“…Few studies have examined EndoMT specifically mediated by SIRTs and, to our knowledge, this is the first to show that SIRT7 loss induces EndoMT in the lung vasculature. SIRT1 loss has been shown to induce EndoMT and upregulate TGFβ levels in human umbilical vein endothelial cells 56 , and SIRT3 KO mice undergo EndoMT in renal fibrosis 57 , both of which support our findings. Several other pathways induced by molecules such as Wnt, Notch1, and Sonic Hh have been described in EndoMT 50 .…”

Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target

“…Mice with SIRT3 loss more easily develop renal dysfunction with increased ROS production and EndoMT. Interestingly, SIRT3 can activate FOXO3a to inhibit this progress 148 . SIRT3 can also inhibit renal fibrosis by deacetylation and activation of GSK3 β to inhibit the expression of fibrosis genes 133 .…”

SIRT3 Deficiency Sensitizes Angiotensin-II-Induced Renal Fibrosis

“…Sirtuin 3 (SIRT3), a mitochondrial nicotinamide adenine dinucleotide (NAD)+-dependent deacetylase, plays a key role in hypertension-induced renal injury [ 12 , 13 ]. Recent studies have shown that SIRT3 activation could alleviate the development of mouse hypertensive renal fibrosis by the suppression of endothelial-to-mesenchymal transition [ 12 ] and that the activation of SIRT3 signaling could ameliorate mouse injury induced by hypertension [ 13 ]. In our previous study, we found that the ablation of SIRT3 caused mouse coronary microvascular dysfunction and impaired cardiac recovery post myocardial ischemia [ 14 ].…”