Ageing is a universal process that affects all organs. Age-related disruptions in cellular homeostasis result in declines in organ functions and in the responsiveness to physiological stress. Renal function gradually declines with age in most healthy individuals , and the amount of glomerular, vascular and interstitial scarring in the renal tissue of healthy adults increases with age . Ageing is a risk factor for end-stage renal failure ; therefore, elucidating the process of renal ageing may support better treatments for both chronic kidney disease (CKD) and acute kidney injury (AKI).
Calorie restriction without malnutrition promotes longevity and slows ageing . One possible mechanism by which calorie restriction exerts beneficial effects involves the actions of sirtuins (SIRTs), especially SIRT1. The activation of SIRT1, which is an NAD+-dependent deacetylase, may lead to the induction of gene silencing, reduction of apoptosis and inflammation, enhanced mitochondrial biogenesis, regulation of glucose/lipid metabolism, induction of autophagy and adaptation to cellular stress, by the deacetylation of histone and more than a dozen nonhistone proteins, including transcription factors and transcriptional coregulatory proteins . SIRT3, which is an NAD+-dependent deacetylase in mitochondria that is induced by calorie restriction, also regulates the antioxidative defense system, metabolism and longevity [5,6]. Therefore, SIRT1 and SIRT3 may improve or retard age-related diseases, including diabetes, cardiovascular diseases, neurodegenerative disorders and kidney diseases. Recent studies show that SIRT1 activation associated with calorie restriction retards the normal ageing process in the kidney, and SIRT1 and SIRT3 act as renoprotective molecules for various kidney disorders in animal models. In this review, we focus on the role of SIRT1 and SIRT3 in the kidneys and discuss the potential of sirtuin-based therapeutics against kidney diseases.
INTESRSTITIAL FIBROSIS, TUBULAR CELL APOPTOSIS AND SIRT1 IN THE KIDNEY
Tubulointerstitial fibrosis is considered to be a central event in the progression of CKD independent of cause. Even in glomerulopathies, tubulointerstitial fibrosis correlates better than glomerular injury with the evolution and prognosis of the kidney disease . The epithelial-to-mesenchymal transition (EMT) plays a pivotal role in the pathogenesis of the development of organ fibrosis, including renal fibrosis . Simic et al.[9▪▪] reported that SIRT1 can reduce EMT in kidney fibrosis by deacetylating Smad4 and repressing the effect of transforming growth factor-β (TGF-β) signalling on matrix metalloproteinase 7 (MMP7), a Smad4 target gene. They found that the reduction of MMP7 expression decreases the amount of cleaved E-cadherin, and β-catenin remains bound to E-cadherin at the cell–cell junctions.
Yuan et al. demonstrated that aldosterone reduced peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α) activity by downregulating its expression but increasing its acetylation and inducing mitochondrial dysfunction in cultured proximal tubular cells. Overexpression of PGC-1α could prevent aldosterone-induced mitochondrial dysfunction and EMT. SIRT1 activation by resveratrol results in the deacetylation of PGC-1α and restores mitochondrial dysfunction and EMT. Li et al. reported that SIRT1 activation by resveratrol inhibited the acetylation of Smad3, resulting in reduction of TGF-β1 induced collagen IV and fibronectin expression in a unilateral ureteral obstruction (UUO) animal model and in cultured cells (rat fibroblasts: NRK49F; rat proximal tubular cells: NRK52E).
Renal tubular cell apoptosis is involved in the progression of kidney injury. He et al. reported that SIRT1 was abundantly expressed in mouse medullary interstitial cells and increased cellular resistance to oxidative stress. Decreased SIRT1 was associated with increased apoptosis and fibrosis after UUO in Sirt1 (+/−) mice, while SIRT1 activation in wild-type mice reduced apoptotic and fibrotic changes in the UUO model. SIRT1 deficiency decreases the induction of cyclooxygenase 2 (COX2) in medullary interstitial cells under oxidative stress, and exogenous prostaglandin E2 reduces apoptosis in oxidatively stressed SIRT1-deficient cells. These findings indicate the protective function of SIRT1 and identify COX2 as a target of SIRT1.
Hasegawa et al. found that SIRT1 protects against oxidative stress induced apoptosis by inducing catalase via deacetylation of FOXO3 in cultured proximal tubular cells. Moreover, they reported that renal proximal tubular cell-specific SIRT1 transgenic mice exhibited resistance to cisplatin-induced renal tubular cell injuries, such as apoptosis, by maintaining peroxisome number and function, concomitant upregulation of catalase and elimination of renal oxidative stress . Another study  showed that SIRT1 activation by resveratrol reduced cisplatin-induced proximal tubular cell apoptosis through deacetylation of p53.
INFLAMMATION AND SIRTUINS IN THE KIDNEY
The inflammatory process is a pivotal mechanism for the initiation and progression of kidney diseases . Therefore, controlling the inflammatory process might be a potential therapeutic target. The nuclear factor-κB (NF-κB) signalling pathway plays a central role in the regulation of inflammatory processes . SIRT1 may act as a negative regulator of NF-κB activity by deacetylating the p65 subunit, which may cause anti-inflammatory effects .
We found that SIRT1 protein expression significantly decreased and the amount of acetylated NF-κB p65 and the inflammation process increased in the kidneys of Wistar fatty diabetic rats (WFRs) compared with Wistar lean nondiabetic rats (WLRs). The increased levels of acetylated NF-κB and inflammation in WFRs were decreased by calorie restriction, which was consistent with the restoration of SIRT1 protein expression in the kidney. Therefore, renal inflammation is induced by increased levels of acetylated NF-κB p65 as a result of the reduced SIRT1 protein expression, while calorie restriction exerts anti-inflammatory effects by restoring SIRT1 expression in the kidneys of WFRs . In addition, Jung et al. reported that the administration of cisplatin in renal proximal tubular cells (HK-2 cells) reduced SIRT1 expression and was associated with increased levels of acetylated NF-κB p65, and that overexpression of SIRT1 ameliorated cisplatin-induced hyperacetylation of NF-κB p65 and cell injury.
Free fatty acid mediated renal lipotoxicity is associated with the progression of tubulointerstitial inflammation in proteinuric kidney disease . Koyama et al. demonstrated that SIRT3 exhibits antioxidant and anti-inflammatory effects under conditions of palmitate-induced lipotoxicity by enhancing the mitochondrial oxidative capacity and antioxidant defenses in proximal tubular cells.
ROLE OF SIRT1 IN GLOMERULAR CELLS
Apoptosis is a distinct form of cell death observed under various physiological and pathological conditions . Glomerular cells, including mesangial cells and podocytes, exhibit enhanced apoptosis in human and experimental kidney diseases. Therefore, suppressing glomerular cell apoptosis may help prevent various kidney diseases.
Podocytes serve as a crucial component of the glomerular filtration barrier. Podocyte loss induced by apoptosis is observed in several kidney diseases and is involved in the pathophysiology of kidney injury. Podocyte apoptosis can be induced by several factors, such as aldosterone and advanced glycation end products (AGEs). Yuan et al.[24▪] reported that the SIRT1/PGC-1α axis in mitochondria ameliorates aldosterone-induced podocyte injuries. They found that aldosterone suppressed SIRT1 and PGC-1α activation in cultured podocytes, which resulted in increased podocyte apoptosis, the loss of slit diaphragm proteins including nephrin and podocin, and mitochondrial dysfunction. SIRT1 activation protected against aldosterone-induced podocyte injuries with mitochondrial dysfunction by inhibiting both apoptosis and the loss of slit diaphragm proteins through deacetylation and activation of PGC-1α. Chuang et al. also found that AGE-modified bovine serum albumin (AGE-BSA) increases FOXO4 acetylation and suppresses the expression of the SIRT1 protein in glomerular podocytes of db/db diabetic mice and diabetic patients. Acetylated FOXO4 promotes the expression of the pro-apoptosis gene Bcl2l11 (also known as Bim) and leads to podocyte apoptosis .
SIRT1 decreases mesangial cell apoptosis induced by oxidative stress by reducing p53 activity  and attenuates TGF-β induced apoptotic signalling mediated by the effector molecule Smad7 . SIRT1-dependent deacetylation of Smad7 also enhances the ubiquitin-dependent proteasomal degradation of Smad7 by Smad ubiquitination regulatory factor1 (Smurf1).
AUTOPHAGY AND SIRT1 IN THE KIDNEY
Autophagy is a lysosomal degradation pathway that plays a crucial role in removing protein aggregates and damaged organelles such as mitochondria to maintain intracellular homeostasis and promote cellular health under various stress conditions, including hypoxia [28,29]. Dysfunction of autophagy is involved in the pathogenesis of age-related disease, including kidney disease . SIRT1 can positively regulate autophagy by deacetylating essential autophagic factors such as autophagy-related gene (Atg)5, Atg7 and light chain3 (LC3) . Furthermore, SIRT1 deacetylates the transcription factor FOXO3a, which leads to enhanced expression of proautophagic BCL2/adenovirus E1V 19-kDa interacting protein 3 (Bnip3) .
We have shown that hypoxia-induced autophagy activity declines with age in mice, which leads to the accumulation of damaged mitochondria and mitochondrial oxidative stress in the kidneys . Interestingly, long-term calorie restriction restores autophagy activity, even in aged kidneys. We found that SIRT1-mediated autophagy is essential in the calorie restriction mediated protection of aged kidneys. Bnip3 expression is essential for inducing autophagy under hypoxic conditions and is positively regulated by FOXO3a; however, regulation is altered in aged kidneys. Calorie restriction mediated SIRT1 activation deacetylates and activates FOXO3a transcriptional activity and subsequent Bnip3-mediated autophagy, even in aged kidneys. Furthermore, the kidneys of Sirt1(+/−) mice exhibit lower autophagy activity and decreased Bnip3 expression and are thereby resistant to calorie restriction mediated antiageing effects. These findings suggest that SIRT1 is essential for calorie restriction mediated renoprotection, which is induced by removing the damaged mitochondria under hypoxic conditions via Bnip3-mediated autophagy. In addition, we noted mitochondrial morphological damages in the proximal tubular cells and p62/Sqstm1 accumulation in the kidneys of diabetic WFRs. p62/Sqstm1 binds to ubiquitylated substrates and LC3 on autophagosomes, and is itself degraded by autophagy ; therefore, the accumulation of p62/Sqstm1 indicates the impairment of autophagy, resulting in mitochondrial damage. Because SIRT1 is a positive regulator of autophagy, decreased SIRT1 expression in diabetic kidneys may lead to dysregulation of autophagy. Calorie restriction improves the function of autophagy, which results in normalization of mitochondrial morphological changes and p62/Sqstm1 accumulation accompanied by the restoration of SIRT1 expression .
ROLE OF SIRTUINS IN Na+ HANDLING AND BLOOD PRESSURE REGULATION
Angiotensin II (Ang II) plays important roles in the pathogenesis of CKD and hypertension. Ang II is a mediator of glomerular haemodynamic adaptation and injury, and exhibits pro-inflammatory actions, which lead to upregulation of chemokines, adhesion molecules and other fibrogenic growth factors, and decline in renal function. Most of the traditional cardiovascular effects of Ang II, such as vasoconstriction and sodium retention, are mediated by angiotensin type 1 receptor subtype (AT1R). SIRT1 may negatively regulate AT1R expression. Miyazaki et al. reported that overexpression of SIRT1 or treatment with resveratrol suppresses AT1R expression by reducing the binding of Sp1 to the AT1R promoter in cultured smooth muscle cells. Resveratrol also suppresses AT1R expression in the aorta and improves Ang II-induced hypertension in mice. Interestingly, the lifespans of Atr1 (−/−) mice are extended compared with wild-type mice, and the expression of SIRT3, but not SIRT1, is significantly increased in the kidneys of Atr1 (−/−) mice . However, the role of SIRT3 in renal ageing remains unclear.
Aldosterone increases renal tubular Na+ absorption by increasing the transcription of the epithelial Na+ channel α-subunit (α-ENaC) in the apical membranes of collecting-duct principal cells. The increased transcription contributes to the pathogenesis of hypertension. SIRT1 represses the expression of α-ENaC in mIMCD3 cells independent of its deacetylase activity . SIRT1 interacts with disruptor of telomeric silencing (Dot)-1, a histone H3K79 methyltransferase, which results in H3K79 hypermethylation in chromatin along the α-ENaC promoter and represses α-ENaC transcription. Treatment with aldosterone decreases SIRT1 mRNA expression, whereas SIRT1 inhibits aldosterone-induced α-ENaC promoter activity independent of mineralocorticoid receptor signalling .
SIRT1 AND AUTOSOMAL-DOMINANT POLYCYSTIC KIDNEY DISEASE
Autosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations in Pkd1 or Pkd2 and is characterized by the development of multiple bilateral renal cysts that replace the normal kidney. Zhou et al.[36▪] reported that SIRT1 is involved in the pathogenesis of ADPKD. Increased SIRT1 expression in Pkd1 mutant renal tubular cells regulates cystic epithelial cell proliferation through deacetylation and phosphorylation of Rb and regulates cystic epithelial cell death through deacetylation of p53 [36▪]. These findings suggest that suppression of SIRT1 using a SIRT1 inhibitor, such as nicotinamide, may be useful to delay cyst formation in ADPKD.
SIRT1 exerts renal protective effects by reducing fibrosis, inhibiting apoptosis and inflammation, inducing autophagy and regulating blood pressure (Fig. 1). Therefore, SIRT1 may be a novel therapeutic target for kidney disease. However, in ADPKD, SIRT1 is involved in the progression of cyst formation (Fig. 1). SIRT3 may have important roles in renoprotection (Fig. 1); however, further investigation into the targets and functions of SIRT3 will aid the development of new strategies for protection against kidney disease.
This work was supported by a grant from a Grant-in-Aid for Scientific Research (C) (24591218) and a Grant for Promoted Research from Kanazawa Medical University (S2013-2) to M. Kitada, a Grant-in-Aid for Scientific Research (B) (25282028), a Grant-in-Aid for Challenging Exploratory Research (25670414) and the 4th Annual Research Award Grant of the Japanese Society of Anti-Aging Medicine to D. Koya.
Conflicts of interest
There are no conflicts of interest.
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