silent information regulator 2 ( sir2 ) is a nicotinamide adenine dinucleotide- ( nad- ) dependent deacetylase that was first discovered in the 1970s in yeast ; sir2 prolongs the lifespan of numerous species . mammals have seven different sirtuins ( sirt1sirt7 ) , which share the same conserved catalytic core region composed of 275 amino acids . the sirt1 gene , composed of 500 amino acid residues , was first discovered in 1999 . h1 twenty - sixth , h3 ninth , and h4 sixteenth lysine , sirt1 also deacetylates target proteins , such as protein 53 , forkhead - box transcription factor 3 , notch , and poly - adp - ribose polymerases . therefore , sirt1 is linked to cellular energy metabolism and cell senescence regulation [ 25 ] . in 1986 , ivy   isolated and identified a gene associated with the lifespan of cells from yeast . she also found the same gene in caenorhabditis elegans and drosophila sp . and named it sir2 . scientists gradually identified a family of proteins that are homologous to sir2 from mammalian cells and referred to them as sirtuins ( sirts ) . in bacterial and mammalian evolution , the first sirt was discovered in the body of the sirt protein and was named sirt1 . since then , six sirt proteins have been found ( sirt2 to sirt7 ) . sirt1 and yeast sir2 , which have the highest homologies , have been extensively studied . sirt1 , a class iii histone deacetylase , is highly conserved from bacteria to humans and is homologous to sir2 in mammals . this gene comprises nine exons and eight introns and is approximately 33  kb long . the 5- and 3-ends of the gene have a nontranslated region that contains p53 and have 1793  bp with no splicing mutation . sirt1 is mainly localised in the nucleus , but it can also be found in the cytoplasm , where it facilitates nuclear cytoplasmic shuttling . this gene is widely expressed in foetal and adult tissues , including fat and muscle tissues of the liver , kidneys , and brain . it is also uniformly expressed in islet cells but is rarely expressed in islet exocrine gland cells . sirt1 has many substrates , such as histone p53 , tumour suppressor transcription factor foxo , af618 , peroxisome proliferator - activated receptor - coactivator-1  , and ku70 . sirt1 mainly utilises deacetylase activity to exert its regulatory effects on various physiological processes , including gene transcription , energy metabolism , cell senescence , glucose metabolism , lipid metabolism , and insulin secretion   ( table 1 ) . sirt1 is highly expressed in medullary tubular cells and moderately expressed in cortical proximal tubular cells . , sirt1 can exert a powerful renal protective effect against ischaemic or toxic substance injury . diabetic nephropathy ( dn ) , a serious complication of diabetes , is a leading cause of mortality in patients with diabetes mellitus . recent studies have shown that sirt1 is closely related to the occurrence and development of dn . maeda et al .   found that four single nucleotide polymorphisms ( snps ) in sirt1 are associated with dn . analysis of the haplotype of sirt1 revealed that 11 sites are closely linked to dn in related snps . high glucose can lead to pathological changes in glomerular mesangial cells , podocytes , and filtration barrier . high blood glucose levels are usually associated with increases in the expression of p38 and cleaved caspase-3 . the intermittent calorie restriction - induced increase in sirt1 expression can significantly reverse the increase in the levels of the two substances ; it can also block the increase in p53 content in the kidneys under hyperglycaemic conditions . na and k - atpase are important indicators of kidney disease because they can reflect the damage level in the basement membrane . yuan et al .   found that ampk deactivation decreases sirt1 expression , consequently reducing na in rat renal proximal tubules and k - atpase activity . another study   speculated that sirt1 regulates the tgf-/smad and erk1/2 pathways and inhibits basement membrane thickening in a diabetic mouse , thereby delaying the progression of early dn . chuang et al .   found that the accumulation of advanced glycation end products in diabetic patients promotes foxo4 acetylation . this phenomenon initiates the transcription of proapoptotic protein bcl-2 , which mediates podocyte apoptosis . in another study , chuang et al . using rna interference - mediated sirt1 knockdown mouse models observed serious albuminuria and mitochondrial dysfunction under diabetic condition , suggesting sirt1 plays a key role in homeostatic maintenance of podocyte under mitochondrial stress / injury condition . moreover , hasegawa et al . revealed that downregulation of sirt1 and upregulation of the tight junction protein claudin-1 by sirt1-mediated epigenetic regulation in podocytes contributed to albuminuria under diabetic condition . on the contrary , increased sirt1 expression protects podocyte against apoptosis induced by the end products of sugar residues . in vivo experiments on db kim et al .   found that the proapoptotic gene bax is downregulated in db / db mice treated with resveratrol through gavage . meanwhile , low phosphorylation levels of pi3k - akt and foxo3a as well as upregulation of the antiapoptotic gene bcl-2 increase superoxide dismutases 1 and 2 ( sod1 and sod2 ) . resveratrol can reverse the apoptosis of mesangial cells induced by glucose and oxidative stress in vitro . a study   found that nad and resveratrol activate sirt1 , which can reverse the hyperglycaemia - induced mesangial cellular senescence . conversely , sirt1 inhibition by sirna or nicotinamide can accelerate the senescence of mesangial cells . kume et al .   found that sirt1 blocks mesangial cell apoptosis induced by oxidative stress and tgf-. kitada et al .   detected a decrease in mitochondrial autophagy in the renal proximal tubule cells of diabetic rats subjected to calorie restriction . these results suggest that sirt1 can prevent renal cell apoptosis under diabetic conditions and thus improve dn . .   found that wistar diabetic rats have lower renal sirt1 expression , higher urinary albumin excretion , lower creatinine clearance rate , and significantly higher contents of acetylated nf-b p65 and inflammatory factors than wistar nondiabetic rats . administration of sirt1 agonists significantly reduces urinary albumin excretion , considerably improves creatinine clearance rate , and significantly decreases inflammatory factors . sirt1 agonists substantially reverse wfr renal inflammation during factor upregulation and macrophage infiltration and then confer renal protection . report that streptozotocin- ( stz- ) induced diabetic rats were gavaged with resveratrol and detected that resveratrol increases sirt1 and foxo1 expression , decreases malondialdehyde and sod activities , and reverses collagen iv and fibronectin synthesis , mesangial matrix accumulation , and glomerular tubular fibrosis . reported that sirt1 perpetrates nephrosclerosis through downregulation of mmp-14 , which is relevant to fibrosis of vascular senescence . in another study , shang et al . injected 3,5-diiodo - l - thyronine ( t2 ) into the peritoneum of stz - induced diabetes rats . compared with the diabetic rats , the experimental rats showed lower blood glucose , urine protein secretion , matrix expansion , tgf-1 , fibronectin , and collagen deposition after 12 weeks . however , the experimental rats had higher sirt1 expression and activity than the control diabetic rats . in the in vitro study , mesangial cells were cultured in a high - glucose medium and showed a substantial decrease in fibronectin expression and collagen synthesis after t2 treatment . however , these in vitro and in vivo results showed renal protective effect of t2 is blocked by the sirt1 inhibitor sirtinol . therefore , t2 not only improves renal structure and function , but also restores sirt1 expression in diabetic rats . sirt1 alleviated dn by reducing renal cell apoptosis , relieving renal inflammation and fibrosis as shown in figure 1 . therefore , the prevention and treatment of acute kidney injury ( aki ) are particularly important . the main side effect of cisplatin is aki , with an incidence rate of 25% to 35% . recent studies have shown that cisplatin - related aki is caused by attenuated antioxidant effects . another study has shown that oxygen free radicals generated by cisplatin initiate oxidative damage in the mitochondria . this phenomenon causes mitochondrial vacuolation and increases the local production of oxygen free radical and the apoptosis of renal tubular cells , eventually resulting in aki . sirt1 upregulates catalase expression to degrade excessive free radicals , increase purine degradation , and promote atp generation . this phenomenon leads to the inhibition of oxidative stress and the prevention of aki . in the second mechanism these phenomena directly affect atp synthesis for lipid metabolism and cell apoptosis , which are important in maintaining normal cell and organ functions . mitochondrial dysfunction is an important pathological process for aki caused by ischaemia or toxic substances . another study suggested that the short - term upregulation of sirt1 in cisplatin - induced acute renal injury protects renal tubular cells against damage through core histone deacetylation or / and dna repair by sirt1 . kim et al .   cultured the proximal tubule cells of cisplatin - treated mice in vivo and confirmed that sirt1 reduces p53 activity by reducing its acetylation level . fan et al .   found that clamping in the renal artery of april - aged mice for 45  min can cause substantial kidney damage , as evidenced by increased serum creatinine and urea nitrogen levels and by the presence of tubular cell necrosis . other studies   have shown that sirt1 expression is significantly higher in young mice than in adult mice . pretreatment with the sirt1 activator srt-1720 can evidently improve the renal tubular injury caused by ischaemia - reperfusion in adult mice . compared with wild - type mice , sirt1 heterozygous mice exhibit more severe renal injury . in the sirt gene uuo model group , the sirt1 expression significantly decreased and was associated with cell apoptosis and interstitial fibrosis . however , administration of the sirt1 agonist resveratrol inhibits cell apoptosis and fibrosis in wild - type uuo mice . furthermore , sirt1 reduces the level of acetylated p53 , upregulates the expression of proliferating cell nuclear antigen , and inhibits the apoptosis of tubular cells by downregulating p21 expression . in the renal proximal tubule , sirt1 expression the kidney is the main metabolism and excretion route of toxins ; lipopolysaccharides ( lpss ) can be reabsorbed by the tubules . hence , high lps concentration affects the structure and function of renal tubular epithelial cells and contributes to the occurrence and development of aki . .   showed that the s1 segment of the proximal tubule is the major uptaking region of endotoxins in vivo . the s2 segment , which is located downstream of the proximal tubule , exhibits serious structural and functional injuries . the sirt1 in s1 cells is upregulated , whereas that in s2 cells is not changed . hasegawa et al .   treated primary renal proximal tubule cells with 400  m tbhp for 6  h to mimic an acute oxidative situation . damage in tubular cells promotes the phosphorylation and acetylation of multiple sites in the n and c terminals of intracellular p53 , respectively . however , sirt1 can reduce its activity by reducing the acetylation level of p53 , thereby cancelling its protective effect . determined that sirt1 exerts a protective effect against inflammatory kidney injury in endotoxaemia by suppressing the activation of stat3 , erk1/2 , and nf-b . the various body organs , particularly the kidney , suffer from different degrees of age - related damage . aging often leads to increased oxidative stress , free radical generation , and decreased antioxidant and free radical - scavenging activities . hao and haase   observed that sirt1 is overexpressed when renal medullary interstitial cells are exposed to high - permeability and low - oxygen environments . sirt1 directly or indirectly controls the activation of foxo1 , foxo3 , and foxo4 through deacetylation and regulates cell response to oxidative stress . by contrast , the aging individual is often accompanied by systemic hypoxia , which is closely related to apoptosis , metabolism , and cell cycle regulation . studies have shown that pi3k and akt activities decrease in the kidneys of aging rats under basal level or stress state . kume et al .   indicated that the body gradually suffers from hypoxia with aging . on the one hand , hypoxia activates the pi3k - akt pathway , inhibits the expression of downstream foxo3 , and decreases sirt1 . on the other hand , hypoxia promotes foxo3 acetylation , increases the expression of downstream target genes ( p27kip1 and bnip3 ) , and reduces transcription . , tgf-1 promotes the combination of hat ( p300 ) and sp1 smad and then upregulates p21 , which is an important factor for glomerular hypertrophy . kume et al .   hypothesised that sirt1 protects the kidney by directly interacting with smad7 and inhibiting the p300-mediated acetylation of its lysine residues . adler et al .   suggested that nf-b can control senescence - specific gene expression and cell cycle through a conservative network system . nf-b activity can upregulate the expression of the cox-2 and tnf- genes , which are important factors of inflammation and kidney senescence . the sirt1 subunit interacts with p65 , resulting in p53 deacetylation and then in nf-b transcription inhibition . liu et al .   found that increased acetylation of p65 and activator of transcription 3 ( stat3 ) mean increased binding with bromodomain and extraterminal ( bet ) proteins . diabetic db / db mice with conditional deletion of sirt1 in podocytes developed more proteinuria , kidney injury , and acetylation of p65 and stat3 compared with db / db mice without sirt1 deletion . these findings indicate that sirt1 exerts a cytoprotective effect by alleviating cell apoptosis and inhibiting inflammatory reaction . extracellular high - mobility group box 1 ( hmgb1 ) , release from stressed kidneys , acts as a potent proinflammatory cytokine that contributes to the pathogenesis of diverse inflammatory . found sirt1 participated in regulating nuclear retention of hmgb1 to ultimately modulate damage signaling initiated by hmgb1 secretion during stress and then eased increased renal damage . numerous studies have shown that sirt1 activity is essential in cancer , neurodegenerative diseases , diabetes , cardiovascular disease , and other age - related diseases . ln is a common autoimmune disease , in which the production of autoimmune antibodies is the key process in its pathogenesis . in addition , the igm and igg immune complexes were found deposited in the kidney and liver of these mice , showing lupus - like symptoms [ 49 , 50 ] . they can produce a significant number of inflammatory cells , such as tnf- , il-6 , and il-1 , during inflammatory response . sirt1 can deacetylate p65 and ap-1 and then inhibit the nf-b pathway , ap-1 transcriptional activity , and cox-2 expression . sirt1 can also reduce the proinflammatory phenotype of macrophages by regulating macrophage - mediated inflammation [ 51 , 52 ] . the unfolded protein response ( upr ) is another important signalling pathway utilised by macrophages . vivo study demonstrated that specific knockout of sirt1 in bone marrow cells ( mac - sirt1 ko ) promotes the acetylation of p65 and renders nf-b hyperacetylated , resulting in increased transcriptional activation of proinflammatory target genes . consistent with increased proinflammatory gene expression , mac - sirt1 ko mice challenged with a high - fat diet display high levels of activated macrophages in liver and adipose tissue , thus indicating that sirt1 plays a pivotal role in regulating the inflammatory , immune , and apoptotic responses . sirt1 affects the activation , proliferation , and apoptosis of t and b lymphocytes by regulating foxo1 , foxo3 , and p53 . sirt1 knockout promotes the proliferation of mouse t cells ; this phenomenon reduces the inhibition of nf-b and ap-1 transcription , which can be activated without the different cd28-stimulated secretions of effector t cells . taken together , these findings indicate that sirt1 regulates the proliferation or apoptosis of numerous cells , thereby affecting the activities of lymphocytes and macrophages that regulate the body 's immune response ( figure 2 ) . taken together , sirt1 depends on nad through the acetylation or phosphorylation of different substrates . it exerts regulatory effects on gene silencing ; cell proliferation , apoptosis , and senescence ; glucose metabolism ; and lipid homeostasis . sirt1 can inhibit the apoptosis induced by kidney cell injuries , reduce renal inflammation , improve mitochondrial function , and reduce oxidative stress . therefore , sirt1 can improve dn and protect the kidney from acute injury , thereby delaying senescence and improving the prognosis of chronic kidney disease . considering the previously reported role of sirt1 in kidney disease , it may become a new therapeutic target of kidney disease including dn . as a result , investigators have carried out studies based on caloric restriction and some sirt1 activators , such as resveratrol or small molecule activator . the results are inspiring : sirt1 does exert renoprotective effects by conferring resistance to cellular stresses such as hypoxia , reducing interstitial fibrosis , inhibiting tubular and glomerular cell apoptosis and inflammation . however , despite a lot of experimental studies including their promising results and since there is presently very little evidence of pharmacological activity in humans , the number of clinical trials and their highlighting results are yet very limited . due to a research of spiegelman   as he mentioned , the pancreas activation of sirt1 can increase the pancreas insulin secretion , resulting in gluconeogenesis in the liver , which may treat diabetes adversely . .   identified that sirt1 broad - spectrum inhibitors have potential to reduce its focusing on adequate levels and tissue / cell - specificity by test on cancer cells . therefore , further investigations , especially ones focusing on adequate levels and tissue / cell - specificity of manipulation of these pathways and human clinical trials , are necessary in the future .
silent information regulator 2 ( sir2 ) is a nicotinamide adenine dinucleotide- ( nad+- ) dependent deacetylase . 
 the homology of sirt1 and sir2 has been extensively studied . 
 sirt1 deacetylates target proteins using the coenzyme nad+ and is therefore linked to cellular energy metabolism and the redox state through multiple signalling and survival pathways . during the past decade , investigators have reported that sirt1 activity is essential in cancer , neurodegenerative diseases , diabetes , cardiovascular disease , and other age - related diseases . in the kidneys 
 , sirt1 may inhibit renal cell apoptosis , inflammation , and fibrosis . 
 therefore its activation may also become a new therapeutic target in the patients with chronic kidney disease including diabetic nephropathy . in this paper 
 , we would like to review the protective functions of sirtuins and the role of sirt1 in the onset of kidney disease based on previous studies , including diabetic nephropathy , acute renal injury , chronic kidney disease as well as lupus nephritis .