Regulation and pathophysiologic role of Sirt3 in renal diseases

Oxidative stress plays a vital role in the pathophysiology of chronic kidney diseases (CKD). Accumulating evidence has demonstrated that oxidative stress plays an important role in kidney fibrosis and inflammation by regulating extracellular matrix production, infiltration of leukocytes in the interstitium, and proliferation of myofibroblasts. Further studies are required to develop new therapeutic strategies and agents to control these events.

A novel and important preliminary finding is that Sirt3, an important class III deacetylase, is downregulated in the diseased kidneys of mice with Adriamycin and obstructive nephropathies. Renal Sirt3 expression is negatively correlated with renal fibrosis and inflammation. Deletion of the Sirt3 gene in mice further enhances the renal fibrosis and inflammation, and deterioration of renal function. In vitro studies also confirmed that overexpression of Sirt3 inhibits TGF-beta-induced fibrosis in tubular epithelial cells and knockdown of the Sirt3 mRNA enhances this induction. Further, the suppressed Id1 induction by TGF-beta may be a possible mechanism for Sirt3-protected renal injury. These new findings indicate that Sirt3 can protect kidney from injury. In addition, Sirt3 expression is negatively correlated with the activation of TGF-β/Smad3 signaling and the expression of HIC1, a transcriptional repressor, suggesting that TGF-β-Smad3-HIC1 axis may suppress renal Sirt3 expression at disease status.

Based on these findings, we hypothesize that TGF-beta/Smad3 suppresses Sirt3 expression by HIC1 upregulation and that Sirt3 suppresses oxidative stress to prevent kidney injury by fibrosis and inflammation. We propose three specific aims to test these hypotheses: 1). We will define the functional role of Sirt3 in renal injury; 2). We will investigate the signaling mechanisms by which TGF-β signaling regulates Sirt3 expression; and 3). We will investigate how Sirt3 prevents kidney injury and explore the therapeutic potential of Sirt3 for renal injury by engineering ectopic expression of Sirt3.

Determining the regulation and pathophysiologic role of Sirt3 in renal injury will uncover a new mechanism of kidney diseases. Notably, overexpression of Sirt3 in the kidney will inhibit renal injury. Although recent advances have led to a much better understanding of these processes, there is as yet no successful strategy which suppresses renal injury. Therefore, therapeutic strategies to combat renal injury are urgently needed. The proposed studies may provide a specific and effective clinical impact in terms of the prevention and treatment of the progression of chronic kidney disease.