The Role of Sirtuins in Kidney Diseases

Shi

et al. 2021

Diabetic Nephropathy

Diabetes is a noncommunicable disease and arguably represents the greatest pandemic in human history. Diabetic kidney disease (DKD) is seen in both type 1 and type 2 diabetes and can be detected in up to 30–50% of diabetic subjects. DKD is a progressive chronic kidney disease (CKD) and is a leading cause of mortality and morbidity in patients with diabetes. Renal fibrosis and inflammation are the major pathological features of DKD. There are a large number of independent and overlapping profibrotic and pro-inflammatory pathways involved in the pathogenesis and progression of DKD. Among these pathways, the transforming growth factor-β (TGF-β) pathway plays a key pathological role by promoting fibrosis. Sirtuin-1 (SIRT1) is a protein deacetylase that has been shown to be renoprotective with an anti-inflammatory effect. It is postulated that a reduction in renal SIRT1 levels could play a key role in the pathogenesis of DKD and that restoration of SIRT1 will attenuate DKD. Cell division autoantigen 1 (CDA1) synergistically enhances the profibrotic effect of TGF-β in DKD by regulating the expression of the TGF-β type I receptor (TβRI). CDA1 has also been found to be an inhibitor of SIRT1 in the DNA damage response. Indeed, targeting CDA1 in experimental DKD not only attenuates diabetes-associated renal fibrosis but also attenuates the expression of key pro-inflammatory genes such as tumor necrosis factor-α (TNF-α) and Monocyte Che moattractant Protein-1 (MCP-1). In conclusion, there is a large body of experimental data to support the view that targeting CDA1 is a superior approach to directly targeting TGF-β in DKD since it is not only safe but also efficacious in retarding both fibrosis and inflammation.

Section: Fibrosis In Dkdmentioning

confidence: 99%

Section: Role Of Sirtuins In Dkdmentioning

confidence: 99%

Key profibrotic and pro-inflammatory pathways in the pathogenesis of diabetic kidney disease

Patel

Shi

et al. 2021

Diabetic Nephropathy

“…SIRT1, a mammalian ortholog highly closed to Sir2, belongs to the Sirtuins family (SIRT1-SIRT7) whose function depends on nicotinamide adenine dinucleotide (NAD+) and is highly conserved in evolution (Hong et al, 2020 ). SIRT1 widely plays a key role in cell survival and apoptosis, inflammatory stress adaptation to cell growth, differentiation, metabolism, and senescence, and prevents mitochondrial dysfunction through regulating its transcriptional activity and protein expression levels by changing the acetylation state of substrates (Jiao and Gong, 2020 ; Chelladurai et al, 2021 ; Lou et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Relieving Cellular Energy Stress in Aging, Neurodegenerative, and Metabolic Diseases, SIRT1 as a Therapeutic and Promising Node

Wang

et al. 2021

Front. Aging Neurosci.

The intracellular energy state will alter under the influence of physiological or pathological stimuli. In response to this change, cells usually mobilize various molecules and their mechanisms to promote the stability of the intracellular energy status. Mitochondria are the main source of ATP. Previous studies have found that the function of mitochondria is impaired in aging, neurodegenerative diseases, and metabolic diseases, and the damaged mitochondria bring lower ATP production, which further worsens the progression of the disease. Silent information regulator-1 (SIRT1) is a multipotent molecule that participates in the regulation of important biological processes in cells, including cellular metabolism, cell senescence, and inflammation. In this review, we mainly discuss that promoting the expression and activity of SIRT1 contributes to alleviating the energy stress produced by physiological and pathological conditions. The review also discusses the mechanism of precise regulation of SIRT1 expression and activity in various dimensions. Finally, according to the characteristics of this mechanism in promoting the recovery of mitochondrial function, the relationship between current pharmacological preparations and aging, neurodegenerative diseases, metabolic diseases, and other diseases was analyzed.

“…Silent information regulator 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD þ )-dependent deacetylase, regulates multiple cellular biological processes, including stress responses, cellular senescence, longevity, apoptosis, and inflammation [15,16]. Interestingly, SIRT1 has recently been identified as a novel therapeutic target for the prevention and treatment of several renal diseases [17][18][19]. Simultaneously, THC has been reported to alleviate diabetic cardiomyopathy mainly by attenuating oxidative stress and fibrosis via increasing the expression of SIRT1 [20].…”

Section: Introductionmentioning

confidence: 99%

Tetrahydrocurcumin protects against sepsis-induced acute kidney injury via the SIRT1 pathway

Liu

et al. 2021

Renal Failure

Sepsis-induced acute kidney injury (AKI) continues to be associated with poor outcomes in critical care patients. Previous research has revealed that tetrahydrocurcumin (THC) exerts renoprotective effects in multiple nephritic disorders by modulating inflammation and oxidative stress. However, the effects of THC on sepsis-induced AKI and the underlying mechanisms remain unclear. In this study, a mouse model of sepsis-induced AKI, generated by cecal ligation and puncture operation, was used to investigate the protective effects of THC and the role of SIRT1. Histological manifestation and TUNEL analysis were observed to determine the severity of kidney damage. Levels of BUN, SCr, KIM-1, and UAlb/Cr were calculated to assess the renal function. Expressions of IL-1b, IL-6, and TNF-a were measured to evaluate the inflammatory response. MDA content, SOD, GSH, CAT, and GPx activities and DHE staining were analyzed to estimate the degree of oxidative stress. Protein expressions of SIRT1, Ac-p65, and Ac-foxo1 were detected to explore the underlying mechanisms. We observed that THC not only increased the survival rate, improved the kidney function and ameliorated the renal histological damage of septic mice, but also inhibited inflammatory response, prohibited oxidative stress, and prevented cell apoptosis in renal tissues in septic mice. Mechanistically, THC remarkably increased the expression of SIRT1, accompanied by decreased expressions of downstream molecules Ac-p65 and Ac-foxo1. Meanwhile, the beneficial effects of THC were clearly abolished by the SIRT1-specific inhibitor EX527. These results delineate that THC prevents sepsis-induced AKI by suppressing inflammation and oxidative stress through activating the SIRT1 signaling.