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Review
. 2018 Oct 17:9:624.
doi: 10.3389/fendo.2018.00624. eCollection 2018.

SIRT1 Is a Potential Drug Target for Treatment of Diabetic Kidney Disease

Yifei Zhong  1 , Kyung Lee  2 , John Cijiang He  2   3
Affiliations
Review

SIRT1 Is a Potential Drug Target for Treatment of Diabetic Kidney Disease

Yifei Zhong et al. Front Endocrinol (Lausanne). .

Abstract

Multiple studies have demonstrated a critical role of Sirtuin-1 (SIRT1) deacetylase in protecting kidney cells from cellular stresses. A protective role of SIRT1 has been reported in both podocytes and renal tubular cells in multiple kidney disease settings, including diabetic kidney disease (DKD). We and others have shown that SIRT1 exerts renoprotective effects in DKD in part through the deacetylation of transcription factors involved in the disease pathogenesis, such as p53, FOXO, RelA/p65NF-κB, STAT3, and PGC1α/PPARγ. Recently we showed that the podocyte-specific overexpression of SIRT1 attenuated proteinuria and kidney injury in an experimental model of DKD, further confirming SIRT1 as a potential target to treat kidney disease. Known agonists of SIRT1 such as resveratrol diminished diabetic kidney injury in several animal models. Similarly, we also showed that puerarin, a Chinese herbal medicine compound, activates SIRT1 to provide renoprotection in mouse models of DKD. However, as these are non-specific SIRT1 agonists, we recently developed a more specific and potent SIRT1 agonist (BF175) that significantly attenuated diabetic kidney injury in type 1 diabetic OVE26 mice. We also previously reported that MS417, a bromodomain inhibitor that disrupts the interaction between the acetyl-residues of NF-κB and bromodomain-containing protein 4 (BRD4) also attenuates DKD. These results suggest that SIRT1 agonists and bromodomain inhibitors could be potential new therapuetic treatments against DKD progression.

Keywords: SIRT1; acetylation; bromodomain inhibitor; diabetic kidney disease; podocytes.

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Figures

Figure 1
Figure 1
Role of SIRT1 in DKD pathogenesis. This schema summarizes how Sirt1 mediates podocyte injury in DKD. The data suggest that Sirt1 expression is reduced in the diabetic glomeruli including podocytes. Reduced SIRT1 expression leads to increased acetylation and activation of transcription factors, such as NF-κB, STAT3, p53, and PGC1α, leading to exacerbated inflammation, senescence/apoptosis, and mitochondrial dysfunction of kidney cells such as podocytes (shown in blue arrows). All these processes interact each other and contribute to the progression of DKD (shown in red arrows). Therefore, SIRT1 agonists or inhibition of transcription factor acetylation through use of bromodomain inhibitors will reverse these diseased processes and could be developed to treat DKD. (formula image): stimulation; (formula image): inhibition; (formula image): interaction.
See this image and copyright information in PMC

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