Acute kidney injury (AKI) substantially increases the risk of developing and worsening chronic kidney disease (CKD). The shift from AKI to CKD is a complex process that involves various cell types, with macrophages playing a key role in responding to renal injury. M1 and M2 macrophages-the two main types of macrophages-have distinct functions at various stages. M1 macrophages induce kidney damage by secreting pro-inflammatory cytokines immediately after injury, whereas M2 macrophages subsequently facilitate kidney tissue repair. The conversion of macrophages from the M1 to M2 subtype is vital for effective repair after renal injury. However, when M2 macrophages infiltrate persistently, they can paradoxically cause fibrosis, thereby complicating recovery. As a key epigenetic regulatory factor, the deacetylase SIRT6 exerts various biological effects through its enzymatic reactions, including the regulation of cellular metabolism, antioxidant stress response, and inhibition of fibrosis. SIRT6 is expressed in all major types of renal resident cells and is demonstrated to protect the kidneys. SIRT6 promotes the transition from the M1 to M2 subtype; nevertheless, this process poses the risk of fibrosis if macrophages remain in the M2 subtype because of the influence of SIRT6. This review aimed (i) to delve into the intricate role of SIRT6 in macrophage polarization toward the M2 subtype in the context of the progression from AKI to CKD and (ii) to explore potential strategies that may effectively target and mitigate the progression from AKI to CKD.

Perturbation of cardiolipin (CL) metabolism is associated with lipid nephrotoxicity. Recent findings provide new insights into the roles of CL-modulating proteins as critical determinants of podocyte function in chronic kidney disease (CKD). We previously demonstrated that Sirtuin 6 (Sirt6) is a compelling target inhibiting Angiotensin II (Ang II)-induced lipid dysregulation in podocytes. However, whether Sirt6 regulates podocyte CL metabolism is unknown.

Renal biopsy specimens of patients with hypertensive nephropathy (HN) were used in this study. Podocyte Sirt6-specific knockout mice were generated using the Cre-loxP system. The effect of Sirt6 on mitochondrial CL metabolism, especially the peroxidation and hydrolysis of CL, was investigated in Ang II-infusion mice and Ang II-induced cultured podocytes.

Sirt6 and outer mitochondrial membrane protein phospholipase D family member 6 (PLD6) were decreased in the glomeruli of patients with HN. Ang II downregulated Sirt6 and PLD6 expression in podocytes in vitro and in vivo. Podocyte-specific deletion of Sirt6 exacerbated lipid droplets formation, CL accumulation and peroxidation, aggravated Ang II-induced mitochondrial dysfunction and cell apoptosis. Mechanically, Sirt6 maintained podocyte CL homeostasis, at least in part through PLD6 signaling-mediated CL metabolism. In addition, cardiolipin antioxidant Szeto-Schiller Peptide 31 (SS-31) treatment inhibited Ang II-induced lipid accumulation and CL peroxidation in podocytes.

Our findings shed light on Sirt6's regulatory mechanisms on podocyte CL metabolism and suggest exploiting the Sirt6-PLD6 axis as a potential therapeutic target for protecting against lipid nephrotoxicity.

The purpose of this study was to show that hyperpolarized (HP) carbon-13 (13C) MRI with multiple co-HP substrates can probe the time course of renal metabolic changes in diabetes.

[1-13C]pyruvate and [1,3-13C2]acetoacetate were co-HP for simultaneous metabolic assessment of cytosolic and mitochondrial compartments, respectively. A custom multi-band spectral-spatial radiofrequency pulse was designed for enhanced detection of downstream metabolites of both substrates. In vivo co-HP 13C kidney spectra were acquired serially in rats with uncontrolled insulin-deficient diabetes over a period of 8 weeks. Time courses of changes in apparent metabolic conversions of [1-13C]pyruvate and [1,3-13C2]acetoacetate were evaluated and compared with routine clinical markers of kidney disease obtained by serum and urine sampling.

Metabolic conversions of both co-HP substrates showed large shifts in diabetic kidney with chronic hyperglycemia. Production of both HP [1-13C]lactate and [1,3-13C2]β-hydroxybutyrate increased over time, with β-hydroxybutyrate signal significantly elevated at 4 weeks, sustained at 8 weeks. Lactate trended higher at 4 weeks, with a larger, significant increase at 8 weeks. Serum and urine markers of renal function were unaltered from baseline throughout the time course, without significant change in serum creatinine nor evidence of albuminuria.

Noninvasive 13C MRI using multiple co-HP metabolic substrates, whose activities are localized to distinct cellular compartments, could enable early detection of diabetic kidney damage.

Diabetic nephropathy (DN) is a leading cause of chronic kidney disease and end-stage renal failure worldwide. Podocytes, essential components of the glomerular filtration barrier (GFB), are profoundly affected in the diabetic milieu, resulting in structural and functional alterations. Concurrently, macrophages, pivotal innate immune cells, infiltrate the diabetic kidney and exhibit diverse activation states influenced by the local environment, playing a crucial role in kidney physiology and pathology. This review synthesizes current insights into how the dynamic cross talk between these two cell types contributes to the progression of DN, exploring the molecular and cellular mechanisms underlying this interaction, with a particular focus on how macrophages influence podocyte survival through various forms of cell death, including apoptosis, pyroptosis, and autophagy. The review also discusses the potential of targeting macrophages to develop more effective treatments for DN.

Diabetic nephropathy (DN) is a major cause of kidney failure, and its incidence is increasing worldwide. Existing studies have shown that mitochondrial dysfunction is potentially related to the pathogenesis of DN. This study aims to explore novel biomarkers related to mitochondrial metabolism that may affect the diagnosis and treatment of DN.

The Gene Expression Omnibus (GEO) database and MitoCarta3.0 database were used to download the DN datasets and mitochondrial metabolism-related genes (MRGs), respectively. Differentially expressed genes (DEGs) were identified using the "limma" R package, and their functional analysis was performed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Important gene modules were identified by weighted gene Coexpression network analysis (WGCNA) clustering. Next, we obtained key genes by intersecting DEGs, important gene modules and MRGs. The ROC curve was employed to assess the sensitivity and specificity of the diagnostic indicators for DN. Finally, the expression of key genes was assessed in the in vitro DN model and the mechanisms of key gene were investigated.

A total of 343 DEGs were identified, with functional analysis revealing a primary focus on metabolic biological processes. A sum of 752 important module genes was ascertained. PDK4, ECH1, and ETFB were selected as key genes. Then, the expression level and specificity of key genes were verified by the GSE104954 dataset, which confirmed the high diagnostic value of PDK4 and ECH1 (AUC>0.9). Finally, the q-PCR, flow cytometry, and Western blot results indicated that key genes were significantly decreased in high glucose induced HK-2 cells. ECH1 could promote fatty acid oxidation and inhibit cell apoptosis, oxidative stress, and inflammation.

This study identified biomarkers related to mitochondrial metabolism in DN, providing new insights and directions for the diagnosis and treatment of DN.

Sirtuin-6 (SIRT6) has a pivotal role in a wide array of cellular biological functions and is linked to the progression of various diseases. Previous findings have identified SIRT6 as a protective modulator against numerous diabetic complications. However, whether SIRT6 exerts a protective role in diabetic foot ulcer (DFU) remains unstudied. This work established a rat model of DFU and evaluated the possible role of SIRT6 in mediating the wound healing in DFU. Marked reductions in SIRT6 levels were observed in wound samples from DFU patients and rats. Increasing SIRT6 expression in wound tissues remarkably decreased wound area, accelerated epithelialisation, increased collagen deposition and improved angiogenesis. Moreover, up-modulation of SIRT6 relieved the oxidative stress and inflammation in DFU rats. The increase of SIRT6 in cultured vascular endothelial cells restrained cell apoptosis, oxidative stress and inflammation elicited by high glucose (HG). HG-impaired migration capacity and angiogenesis of vascular endothelial cells was also recovered by increasing SIRT6 expression. Mechanism research revealed that SIRT6 overexpression reinforced the activation of the Nrf2 pathway in wound tissues of DFU rats and HG-exposed vascular endothelial cells. Pharmacological suppression of Nrf2 reversed the protective effect of SIRT6 overexpression on HG-triggered endothelial dysfunction. The findings of this work indicate that the positive role of SIRT6 in DFU wound healing is related to Nrf2 activation which contributes to the suppression of oxidative stress and inflammation and the improvement of angiogenesis in vascular endothelial cells. This study highlights the previously unaddressed role of SIRT6 in DFU wound healing, providing novel insights into its protective functions. The findings hold significant clinical value by identifying SIRT6 as a promising therapeutic target for improving DFU wound healing.

Chronic stress is one of the potential causes of the progression of metabolic syndrome (MS). Chronic stress decreases the release of Sirtuin-6 (SIRT6), which regulates MS by controlling glucose, insulin, lipids, and hypertension. Vagus nerve stimulation (VNS) activates SIRT6 via the cholinergic anti-inflammatory pathway (CAP). However, the effectiveness of VNS therapy for treating MS induced by chronic stress has not yet been studied. In this study, we first validated a rat model of chronic unpredictable stress (CUS) and assessed the characteristic features of MS. The CUS rats were exposed to random stressors daily for 8 weeks. The stress response was then confirmed by behavioral alteration and elevated serum corticosterone levels in rats, as measured by various behavioral tests and an ELISA kit, respectively. The MS characteristics in CUS rats were assessed using measurements of fasting blood glucose (FBG), systolic blood pressure (SBP), lipid indices, insulin levels, and HOMA-IR. The stressed animals demonstrated a rise in FBG, SBP, and insulin along with altered lipid indices. After CUS, the rats were treated with VNS (6 Hz, 1.0 ms, 6 V, for 40 min × 14 days, alternatively), and their metabolic activity and vagal flow were assessed. Moreover, SIRT6 and AMP-activated protein kinase (AMPK) expression in rats was also assessed by immunohistochemistry and mRNA expression of liver and pancreatic tissue. SIRT6 and AMPK expression was decreased in CUS animals. Interestingly, VNS treatment attenuated CUS induced MS-associated parameters. These results indicate that VNS may be a beneficial complementary and non-pharmacological method for managing CUS-associated MS.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), affecting over 40% of patients with diabetes. DKD progression involves fibrosis and damage to glomerular and tubulointerstitial regions, with mitochondrial dysfunction playing a critical role. Impaired mitochondria lead to reduced adenosine triphosphate (ATP) production, damaged mitochondria accumulation, and increased reactive oxygen species (ROS), contributing to renal deterioration. Maintaining mitochondrial quality control (MQC) is essential for preventing cell death, tissue injury, and kidney failure. Recent clinical trials show that enhancing MQC can alleviate DKD. However, current treatments cannot halt kidney function decline, underscoring the need for new therapeutic strategies. Mitochondrial-targeted drugs show potential; however, challenges remain because of adverse effects and unclear mechanisms. Future research should aim to comprehensively explore therapeutic potential of MQC in DKD. This review highlights the significance of MQC in DKD treatment, emphasizing the need to maintain mitochondrial quality for developing new therapies.

SIRT6 is a NAD+-dependent histone deacetylase with crucial roles in controlling DNA damage repair, telomere homeostasis, oxidative stress, autophagy, and other cellular processes, and it has long been recognized as a longevity-associated protein. This review details its anti-aging-related mechanisms. First, SIRT6 facilitates DNA repair pathways and maintains genome stability by deacetylating histone H3 at K56, K9, and K18 residues, in addition to participating in DNA damage repair through mono-ADP-ribosylation and other mechanisms. Second, SIRT6 preserves telomere integrity and mitigates cellular senescence by reducing oxidative stress-induced damage through the regulation of reactive oxygen species (ROS), inhibition of inflammation, and other pathways. Furthermore, SIRT6 promotes autophagy, slowing cellular senescence via the modulation of various signaling pathways, including AMPK, IGF-Akt-mTOR, H133Y, IL-1β, and mitochondrial autophagy-related proteins. Finally, SIRT6 regulates multiple signaling pathways, such asNF-κB, FOXO, and AMPK, to counteract the aging process. This review particularly delves into the interplay between SIRT6 and various diseases, including tumors, cardiovascular diseases (e.g., atherosclerosis, heart failure), metabolic diseases (e.g., type 2 diabetes, dyslipidemia, gluconeogenesis, osteoporosis), and neurodegenerative diseases (e.g., Alzheimer's disease). Moreover, recent advancements in SIRT6-regulated compounds (e.g., C3G, BZBS, Fisetin, FNDC5, Lycorine hydrochloride, and Ergothioneine) are discussed as potential therapeutic agents for these mediated diseases.

Sirtuins (SIRTs) are NAD+-dependent deacetylases that mediate post-translational modifications of proteins. Seven members of the SIRT family have been identified in mammals. Importantly, SIRTs interact with numerous metabolic and inflammatory pathways. Thus, researchers have investigated their role in metabolic and inflammatory disorders.

In this review, we comprehensively discuss the involvement of SIRTs in the processes of pancreatic β-cell dysfunction, glucose tolerance, insulin secretion, lipid metabolism, and adipocyte functions. In addition, we describe the current evidence regarding modulation of the expression and activity of SIRTs in diabetes, diabetic complications, and obesity.

The development of specific SIRT activators and inhibitors that exhibit high selectivity toward specific SIRT isoforms remains a major challenge. This involves the need to elucidate the physiological pathways involving SIRTs, as well as their important role in the development of metabolic disorders. Molecular modeling techniques will be helpful to develop new compounds that modulate the activity of SIRTs, which may contribute to the preparation of new drugs that selectively target specific SIRTs. SIRTs hold promise as potential targets in metabolic disease, but there is much to learn about specific modulators and the final answers will await clinical trials.

Apart from the classic features, it is almost unknown whether there exist other new pathological features during pre-metastatic niche formation in hepatocellular carcinoma (HCC). Our previous works have highlighted the contribution of increased matrix stiffness to lung pre-metastatic niche formation and metastasis in HCC. However, whether increased matrix stiffness influences glucose metabolism and supply of lung pre-metastatic niche remains largely unclear. Here we uncover the underlying mechanism by which matrix stiffness-tuned exosomal miRNAs as the major contributor modulate glucose enrichment during lung pre-metastatic niche formation through decreasing the glucose uptake and consumption of lung fibroblasts and increasing angiogenesis and vascular permeability. Our findings suggest that glucose enrichment, a new characteristic of the lung pre-metastatic niche triggered by matrix stiffness-tuned exosomal miRNAs, is essential for the colonization and survival of metastatic tumor cells, as well as subsequent metastatic foci growth.

Diabetic nephropathy (DN) has gradually become one of the main causes of end-stage renal disease (ESRD). However, there is still a lack of effective preventive measures to delay its progression. As the energy factory in the cell, mitochondria play an irreplaceable role in maintaining cell homeostasis. Interestingly, recent studies have shown that in addition to maintaining homeostasis in cells in which mitochondria reside, when mitochondrial perturbations occur in one tissue, distal tissues can also sense and act through mitochondrial stress response pathways through a group of proteins or peptides called "mitokines". Here, we reviewed the mitokines that have been found thus far and summarized their research progress in DN. Finally, we explored the possibility of mitokines as potential therapeutic targets for DN.

SIRT6 is known to play a protective role in several kidney diseases; however, its role in vancomycin-induced renal injury remains unclear. This study aims to confirm the role and related mechanisms of SIRT6 in vancomycin-induced renal injury. To develop a kidney damage model, mice were given vancomycin injections for seven days. Additionally, an in vivo transfection with a SIRT6 overexpression plasmid was performed. PCR and Western blot analyses were used to assess the SIRT6 mRNA and protein expression levels in renal tissue. HE staining was performed to evaluate renal tissue damage, while Scr and BUN were measured using specialized kits. Renal tissue apoptotic cells were labeled using a TUNEL kit, and the levels of the antioxidant enzymes SOD and GSH were measured using appropriate kits. Western blot was used to identify HIPK2, p-p53, and p53 protein expression in the renal tissue. The results reveal that SIRT6 is expressed at markedly low levels in renal tissue. Furthermore, mice administered vancomycin exhibited a significant increase in Scr and BUN levels, indicating impaired renal function. Histological examination through HE staining demonstrated considerable damage to the renal tissue of the vancomycin group. Additionally, the renal tissue of the mice in the vancomycin group displayed reduced levels of the antioxidant enzymes SOD and GSH, an increased number of TUNEL-positive cells, and significantly elevated levels of HIPK2 and p-p53 protein expression. Moreover, the mice transfected with SIRT6 exhibited significant improvements in previously described symptoms. These findings imply that the inhibition of HIPK2/p53 by SIRT6 may represent a promising therapeutic strategy for alleviating vancomycin-induced nephrotoxicity.

Acute kidney injury induced by stings from multiple wasps is a medical emergency and is a driving factor of acute renal dysfunction. Numerous studies have shown that mitochondrial reactive oxygen species (mtROS) play a key role in ischemia-reperfusion injury-, cisplatin-, and sepsis-induced acute kidney injury. However, the role of mtROS and its underlying mechanisms in wasp-venom-induced acute kidney injury remain inconclusive. In this study, we investigated the role and mechanisms of mtROS in mitochondrial damage and inflammation in a mouse model of acute kidney injury induced using wasp venom. Changes in mitochondrial function, transcription factor A (TFAM) expression, and DNA maintenance levels, renal function, stimulator of interferon gene (STING) expression, and inflammatory mediator levels in model mice with or without the mtROS scavenger Mito-Tempo were analyzed in vivo. Downregulation of mtROS levels reversed renal damage and mitochondrial dysfunction, and reduced STING expression and inflammation in the kidneys of model mice. The suppression of mtROS levels also improved the decrease in TFAM levels and mitochondrial DNA copy numbers in the kidneys of the model mice. In summary, the existing evidence in this study shows that mtROS contribute significantly to mitochondrial damage and inflammation in acute kidney injury induced by wasp venom.

To study the role of microRNA (miR)-30d-5p in high glucose-induced podocyte injury.

Podocytes were hyperglycated with 30 mmol/L glucose, transfected with miR-30d-5p inhibitor and mimic, and then treated with 1 mg/mL 3-methyladenine (3-MA). The transfection efficiency of miR-30d-5p was quantified by reverse transcription PCR. Apoptosis was detected by flow cytometry. The expressions of nephrin, microtubule-associated protein light chain (LC) 3Ⅱ/LC3Ⅰ, P62, autophagy-related gene (ATG) 5, PTEN induced putative kinase (PINK) 1 and Parkin gene (PARK2) were detected by Western blotting. The mito-chondrial membrane potential was detected by JC-1 fluorescent probe, and adenosine triphosphate (ATP) content in cells was detected by relevant kits.

Under high glucose induction, podocyte apoptosis increased, miR-30d-5p and P62 expressions were upregulated, while nephrin, ATG5, PINK1, PARK2 and LC3Ⅱ/LC3Ⅰ expressions decreased (all P<0.01). MiR-30d-5p inhibitor reversed the effect of high glucose on apoptosis, and the expression of ATG5, PINK1, PARK2, nephrin, LC3Ⅱ/LC3Ⅰ and P62 (all P<0.01). High glucose induced loss of mitochondrial membrane potential and ATP content in podocytes, while inhibition of miR-30d-5p increased them. Autophagy inhibitors 3-MA and miR-30d-5p mimics reversed the effects of miR-30d-5p inhibition on apoptosis, autophagy and mitochondrial function of podocytes induced by high glucose (all P<0.05).

Inhibition of miR-30d-5p may promote mitochondrial autophagy (mitophagy) by promoting the expression of ATG5, PINK1, PARK2 and alleviating high glucose-induced podocyte damage.

Silica nanoparticles (SiNPs) are widely used in biomedical fields, such as drug delivery, disease diagnosis, and molecular imaging. An increasing number of consumer products containing SiNPs are being used without supervision, and the toxicity of SiNPs to the human body is becoming a major problem. SiNPs contact the human body in various ways and cause damage to the structure and function of genetic material, potentially leading to carcinogenesis, teratogenicity and infertility. This review summarizes SiNPs-induced genetic and epigenetic toxicity, especially to germ cells, and explore their potential mechanisms. SiNPs cause genetic material damage mainly by inducing oxidative stress. Furtherly, the molecular mechanisms of epigenetic toxicity are discussed in detail for the first time. SiNPs alter DNA methylation, miRNA expression, histone modification and inhibit chromatin remodeling by regulating epigenetic-related enzymes and transcription factors. This review is beneficial for investigating potential solutions to avoid toxicity and provide guidance for better application of SiNPs in the biomedical field.

Sirt6, reactive oxygen species and ferroptosis may participate in the pathogenesis of Diabetic Nephropathy (DN). Exploring the relationship between Sirt6, oxidative stress, and ferroptosis provides new scientific ideas to DN.

Human podocytes were stimulated with 30 mM glucose and 5.5 mM glucose. The mice of db/db group were randomly divided into two groups:12 weeks and 16 weeks. Collect mouse blood and urine specimens and renal cortices for investigations. HE, Masson, PAS and immunohistochemical staining were used to observe pathological changes. Western blot, RT-qPCR and immunofluorescence staining were used to evaluate expression of relevant molecules. CCK8 method was introduced to observe cell viability. The changes of podocyte mitochondrial membrane potential and mitochondrial morphology in each group were determined by JC-1 staining and Mito-Tracker.

The expression level of Sirt6, Nrf2, SLC7A11, HO1, SOD2 and GPX4 were reduced, while ACSL4 was increased in DN. Blood glucose, BUN, Scr, TG, T-CHO and 24h urine protein were upregulated, while ALB was reduced in diabetic group. The treatment of Ferrostatin-1 significantly improved these changes, which proved ferroptosis was involved in the development of DN. Overexpression of Sirt6 might ameliorate the oxidation irritable reaction and ferroptosis. Sirt6 plasmid transfection increased mitochondrial membrane potential and protected morphology and structure of mitochondria. The application of Sirt6 siRNA could aggravated the damage manifestations.

High glucose stimulation could decrease the antioxidant capacity and increase formation of ROS and lipid peroxidation. Sirt6 might alleviate HG-induced mitochondrial dysfunction, podocyte injury and ferroptosis through regulating Nrf2/GPX4 pathway.

Podocyte injury plays an important role in the occurrence and progression of diabetic kidney disease (DKD), which leads to albuminuria. Cytoskeletal remodeling is an early manifestation of podocyte injury in DKD. However, the underlying mechanism of cytoskeletal remodeling has not been clarified. Histone deacetylase sirtuin6 (Sirt6) has been found to play a key role in DKD progression, and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) pathway directly regulates the cytoskeletal structure of podocytes. Whereas, the relationship between Sirt6, the PI3K/AKT pathway and DKD progression remains unclear.

Renal injury of db/db mice was observed by PAS staining and transmission electron microscope. Expression of Sirt6 in the glomeruli of db/db mice was detected by immunofluorescence. UBCS039, a Sirt6 activator, was used to explore the renal effects of Sirt6 activation on diabetic mouse kidneys. We also downregulating Sirt6 expression in podocytes using the Sirt6 inhibitor, OSS_128167, and induced upregulation of Sirt6 using a recombinant plasmid, after which the effects of Sirt6 on high glucose (HG)-induced podocyte damage were assessed in vitro. Podocyte cytoskeletal structures were observed by phalloidin staining. The podocyte apoptotic rate was assessed by flow cytometry, and PI3K/AKT signaling activation was measured by Western blotting.

Db/db mice exhibited renal damage including elevated urine albumin-to-creatinine ratio (ACR), increased mesangial matrix, fused podocyte foot processes, and thickened glomerular basement membrane. The expression of Sirt6 and PI3K/AKT pathway components was decreased in db/db mice. UBCS039 increased the expressions of Sirt6 and PI3K/AKT pathway components and ameliorated renal damage in db/db mice. We also observed consistent Sirt6 expression was in HG-induced podocytes in vitro. Activation of the PI3K/AKT pathway via a Sirt6 recombinant plasmid ameliorated podocyte cytoskeletal remodeling and apoptosis in HG-treated immortalized human podocytes in vitro, whereas Sirt6 inhibition by OSS_128167 accelerated HG-induced podocyte damage in vitro.

Sirt6 protects podocytes against HG-induced cytoskeletal remodeling and apoptosis through activation of the PI3K/AKT signaling pathway. These findings provide evidence supporting the potential efficacy of Sirt6 activation as a promising therapeutic strategy for addressing podocyte injury in DKD.

Podocyte injury is a critical event in the pathogenesis of diabetic nephropathy (DN). Hyperglycemia, oxidative stress, inflammation, and other factors contribute to podocyte damage in DN. In this study, we demonstrate that signaling regulatory protein alpha (SIRPα) plays a pivotal role in regulating the metabolic and immune homeostasis of podocytes. Deletion of SIRPα in podocytes exacerbates, while transgenic overexpression of SIRPα alleviates, podocyte injury in experimental DN mice. Mechanistically, SIRPα downregulation promotes pyruvate kinase M2 (PKM2) phosphorylation, initiating a positive feedback loop that involves PKM2 nuclear translocation, NF-κB activation, and oxidative stress, ultimately impairing aerobic glycolysis. Consistent with this mechanism, shikonin ameliorates podocyte injury by reducing PKM2 nuclear translocation, preventing oxidative stress and NF-κB activation, thereby restoring aerobic glycolysis.

This study investigates the potential of 4-hexylresorcinol (4HR) as a novel antidiabetic agent by assessing its effects on blood glucose levels, Glut4 expression, AMPK phosphorylation, and Histone H3 acetylation (Ac-H3) in the liver. In vitro experiments utilized Huh7 and HepG2 cells treated with varying concentrations of 4HR. Glut4, p-AMPK, and Ac-H3 expression levels were quantified via Western blotting. Additionally, GAPDH activity and glucose uptake were evaluated. In vivo experiments employed streptozotocin (STZ)-induced diabetic rats, with or without 4HR treatment, monitoring blood glucose, body weight, and hepatic levels of Glut4, p-AMPK, and Ac-H3. In vitro, 4HR treatment increased GAPDH activity and glucose uptake. Elevated Glut4, p-AMPK, and Ac-H3 levels were observed 8 h after 4HR administration. Inhibition of p-AMPK using compound C reduced 4HR-mediated Glut4 expression. In STZ-induced diabetic rats, 4HR significantly upregulated Glut4, p-AMPK, and Ac-H3 expression in the liver. Periodic 4HR injections mitigated weight loss and lowered blood glucose levels in STZ-injected animals. Histological analysis revealed increased glycogen storage in hepatocytes of the 4HR-treated group. Overall, 4HR enhanced Glut4 expression through upregulation of AMPK activity and histone H3 acetylation in vitro and in vivo, improving hepatic glucose homeostasis and suggesting potential as a candidate for diabetes treatment.

Diabetic nephropathy (DN) is a common and serious complication of diabetes, contributing significantly to patient mortality. Complication of DN (CDN) ranks as the second leading cause of end-stage renal disease globally. To address this, understanding the genetic regulation underlying DN is crucial for personalized treatment strategies. In this study, we identified genes and lncRNAs associated with diabetes and diabetic nephropathy constructing a DN-related lncRNA-mRNA network (DNLMN). This network, characterized by scale-free biomolecular properties, generated through the study of topological properties, elucidates key regulatory interactions. Enrichment analysis of important network modules revealed critical biological processes and pathways involved in DN pathogenesis. In the second step, we investigated the differential expression and co-expression of hub nodes in diseased and normal individuals, identifying lncRNA-mRNA relationships implicated in disease regulation. Finally, we gathered DN-related single nucleotide polymorphisms (SNPs) and lncRNAs from the LincSNP 3.0 database. The DNLMN encompasses SNP-associated lncRNAs, and transcription factors (TFs) linked to differentially expressed lncRNAs between diseased and normal samples. These results underscore the significance of biomolecular networks in disease progression and highlighting the role of biomolecular variability contributes to personalized disease phenotyping and treatment.

Podocyte injury causes proteinuria and accelerates glomerular sclerosis during diabetic kidney disease (DKD). Disruptor of telomeric silencing 1-like (DOT1L), an evolutionarily conserved histone methyltransferase, has been reported in preventing kidney fibrosis in chronic kidney disease models. However, whether DOT1L exerts beneficial effects in diabetes induced podocyte injury and the underlying molecular mechanisms need further exploration.

The expression of DOT1L was confirmed by Western blotting in MPC-5 cells and cortex of kidney from db/db mice, as well as immunofluorescence staining in human renal biopsy samples. The effect of DOT1L on podocyte injury was obtained using MPC-5 cells and db/db mice. The potential target genes regulated by DOT1L was measured by RNA-sequencing. Then, a series of molecular biological experiments was performed to investigate the regulation of PLCL1 by DOT1L in MCP-5 cells and db/db mice. Lipid accumulation was assessed by UPLC-MS/MS analysis and Oil Red O staining.

DOT1L expression was significantly declined in high glucose (HG)-treated MPC-5 cells, podocyte regions of kidney tissues from db/db mice and human renal biopsy samples. Subsequent investigations revealed that upregulation of DOT1L ameliorated HG-induced cell apoptosis in MPC-5 cells as well as primary podocytes. Furthermore, podocyte-specific DOT1L overexpression inhibited diabetic podocyte injury in db/db mice. Mechanistically, we revealed that DOT1L upregulated phospholipase C-like 1 (PLCL1) expression by mediating H3K79me2 at its promoter and PLCL1 silencing suppressed the protective role of DOT1L on podocyte injury. Moreover, DOT1L improved diabetes induced abnormal fatty acid metabolism in podocytes and PLCL1 knockdown reversed its protective effects.

Taken together, our results indicate that DOT1L protects podocyte injury via PLCL1-mediated fatty acid metabolism and provides new insights into the therapeutic target of DKD.

The protection of the diabetic kidney by Empagliflozin (EMPA) is attributed to its interaction with the sodium glucose cotransporter 2 located on proximal tubular epithelial cells (PTECs). Estrogen-related receptor α (ESRRA), known for its high expression in PTECs and association with mitochondrial biogenesis, plays a crucial role in this process. This study aimed to explore the impact of ESRRA on mitochondrial mass in diabetic tubular injury and elucidate the mechanism underlying the protective effects of EMPA.

Mitochondrial changes in PTECs of 16-week-old diabetic mice were assessed using transmission electron microscopy (TEM) and RNA-sequences. In vivo, EMPA administration was carried out in db/db mice for 8 weeks, while in vitro experiments involved modifying ESRRA expression in HK2 cells using pcDNA-ESRRA or EMPA.

Evaluation through TEM revealed reduced mitochondrial mass and swollen mitochondria in PTECs, whereas no significant changes were observed under light microscopy. Analysis of RNA-sequences identified 110 downregulated genes, including Esrra, associated with mitochondrial function. Notably, ESRRA overexpression rescued the loss of mitochondrial mass induced by high glucose (HG) in HK2 cells. EMPA treatment ameliorated the ultrastructural alterations and mitigated the downregulation of ESRRA both in db/db mice and HG-treated HK2 cells.

The diminished expression of ESRRA is implicated in the decline of mitochondrial mass in PTECs during the early stages of diabetes, highlighting it as a key target of EMPA for preventing the progression of diabetic kidney injury.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis causes a high mortality rate and current treatment focuses on supportive therapies but lacks specific therapeutic targets. Notably, sirtuins (SIRTs) shows potential clinical application in the treatment of sepsis. It has been demonstrated that SIRTs, the nicotinamide adenine dinucleotide+(NAD+)-dependent deacetylases that regulate key signaling pathways in eukaryotes and prokaryotes, are involved in a variety of biological processes. To date, seven mammalian yeast Sir2 homologs have been identified. SIRTs can regulate inflammation, oxidative stress, apoptosis, autophagy, and other pathways that play important roles in sepsis-induced organ dysfunction. However, the existing studies on SIRTs in sepsis are too scattered, and there is no relevant literature to integrate them. This review innovatively summarizes the different mechanisms of SIRTs in sepsis organ dysfunction according to the different systems, and focuses on SIRT agonists, inhibitors, and targeted drugs that have been proved to be effective in the treatment of sepsis, so as to integrate the clinical research and basic research closely. We searched PubMed for all literature related to SIRTs and sepsis since its inception using the following medical subject headings: sirtuins, SIRTs, and sepsis. Data on the mechanisms of SIRTs in sepsis-induced organ damage and their potential as targets for disease treatment were extracted.

Renal injury, a prevalent clinical outcome with multifactorial etiology, imposes a substantial burden on society. Currently, there remains a lack of effective management and treatments. Extensive research has emphasized the diverse biological effects of natural polysaccharides, which exhibit promising potential for mitigating renal damage. This review commences with the pathogenesis of four common renal diseases and the shared mechanisms underlying renal injury. The renoprotective roles of polysaccharides in vivo and in vitro are summarized in the following five aspects: anti-oxidative stress effects, anti-apoptotic effects, anti-inflammatory effects, anti-fibrotic effects, and gut modulatory effects. Furthermore, we explore the structure-activity relationship and bioavailability of polysaccharides in relation to renal injury, as well as investigate their utility as biomaterials for alleviating renal injury. The clinical experiments of polysaccharides applied to patients with chronic kidney disease are also reviewed. Broadly, this review provides a comprehensive perspective on the research direction of natural polysaccharides in the context of renal injury, with the primary aim to serve as a reference for the clinical development of polysaccharides as pharmaceuticals and prebiotics for the treatment of kidney diseases.

Many inflammatory disorders, including diabetic kidney disease (DKD), are associated with pyroptosis, a type of inflammation-regulated cell death. The purpose of this work was to ascertain the effects of apabetalone, which targets BRD4, a specific inhibitor of the bromodomain (BRD) and extra-terminal (BET) proteins that target bromodomain 2, on kidney injury in DKD. This study utilized pharmacological and genetic approaches to investigate the effects of apabetalone on pyroptosis in db/db mice and human tubular epithelial cells (HK-2). BRD4 levels were elevated in HK-2 cells exposed to high glucose and in db/db mice. Modulating BRD4 levels led to changes in the generation of inflammatory cytokines and cell pyroptosis linked to NLRP3 inflammasome in HK-2 cells and db/db mice. Likewise, these cellular processes were mitigated by apabetalone through inhibition BRD4. Apabetalone or BRD4 siRNA suppressed PLK1 expression in HK-2 cells under high glucose by P300-dependent H3K27 acetylation on the PLK1 gene promoter, as demonstrated through chromatin immunoprecipitation and immunoprecipitation assays. To summarize, apabetalone relieves renal proptosis and fibrosis in DKD. BRD4 regulates the P300/H3K27ac/PLK1 axis, leading to the activation of the NLRP3 inflammasome and subsequent cell pyroptosis, inflammation, and fibrosis. These results may provide new perspectives on DKD treatment.

Anti-partial epithelial-mesenchymal transition (pEMT) treatment of renal tubular epithelial cells (TECs) represents a promising therapeutic approach. Hyperuricemia nephropathy (HN) arises as a consequence of hyperuricemia (HUA)-induced tubulointerstitial fibrosis (TIF). Studies have suggested that the Ras homolog member A (RhoA)/Rho-associated kinase (ROCK) pathway is a crucial signaling transduction system in renal fibrosis. Fasudil, a RhoA/ROCK inhibitor, has exhibited the potential to prevent fibrosis progress. However, its impact on the pEMT of TECs in HN remains unclear. Here, an HN rat model and an uric acid (UA)-stimulated human kidney 2 (HK2) cell model were established and treated with Fasudil to explore its effects. Furthermore, the underlying mechanism of action involved in the attenuation of pEMT in TECs by Fasudil during HN was probed by using multiple molecular approaches. The HN rat model exhibited significant renal dysfunction and histopathological damage, whereas in vitro and in vivo experiments further confirmed the pEMT status accompanied by RhoA/ROCK pathway activation and oxidative stress in tubular cells exposed to UA. Notably, Fasudil ameliorated these pathological changes, and this was consistent with the trend of ROCK silencing in vitro. Mechanistically, we identified the Neh2 domain of nuclear factor erythroid 2-related factor 2 (Nrf2) as a target of Fasudil for the first time. Fasudil targets Nrf2 activation and antagonizes oxidative stress to attenuate the pEMT of TECs in HN. Our findings suggest that Fasudil attenuates oxidative stress-induced pEMT of TECs in HN by targeting Nrf2 activation. Thus, Fasudil is a potential therapeutic agent for the treatment of HN.

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes and the main cause of end-stage renal disease around the world. Mitochondria are the main organelles responsible for producing energy in cells and are closely involved in maintaining normal organ function. Studies have found that a high-sugar environment can damage glomeruli and tubules and trigger mitochondrial dysfunction. Meanwhile, animal experiments have shown that DKD symptoms are alleviated when mitochondrial damage is targeted, suggesting that mitochondrial dysfunction is inextricably linked to the development of DKD. This article describes the mechanisms of mitochondrial dysfunction and the progression and onset of DKD. The relationship between DKD and mitochondrial dysfunction is discussed. At the same time, the progress of DKD treatment targeting mitochondrial dysfunction is summarized. We hope to provide new insights into the progress and treatment of DKD.

Cardiovascular diseases (CVDs) can be described as a global health emergency imploring possible prevention strategies. Although the pathogenesis of CVDs has been extensively studied, the role of mitochondrial dysfunction in CVD development has yet to be investigated. Diabetic cardiomyopathy, ischemic-reperfusion injury, and heart failure are some of the CVDs resulting from mitochondrial dysfunction Recent evidence from the research states that any dysfunction of mitochondria has an impact on metabolic alteration, eventually causes the death of a healthy cell and therefore, progressively directing to the predisposition of disease. Cardiovascular research investigating the targets that both protect and treat mitochondrial damage will help reduce the risk and increase the quality of life of patients suffering from various CVDs. One such target, i.e., nuclear sirtuin SIRT6 is strongly associated with cardiac function. However, the link between mitochondrial dysfunction and SIRT6 concerning cardiovascular pathologies remains poorly understood. Although the Role of SIRT6 in skeletal muscles and cardiomyocytes through mitochondrial regulation has been well understood, its specific role in mitochondrial maintenance in cardiomyocytes is poorly determined. The review aims to explore the domain-specific function of SIRT6 in cardiomyocytes and is an effort to know how SIRT6, mitochondria, and CVDs are related.

Diabetes mellitus (DM) is a chronic endocrine disorder that poses a long-term risk to human health accompanied by serious complications. Common antidiabetic drugs are usually accompanied by side effects such as hepatotoxicity and nephrotoxicity. There is an urgent need for natural dietary alternatives for diabetic treatment. Tea (Camellia sinensis) consumption has been widely investigated to lower the risk of diabetes and its complications through restoring glucose metabolism homeostasis, safeguarding pancreatic β-cells, ameliorating insulin resistance, ameliorating oxidative stresses, inhibiting inflammatory response, and regulating intestinal microbiota. It is indispensable to develop effective strategies to improve the absorption of tea active compounds and exert combinational effects with other natural compounds to broaden its hypoglycemic potential. The advances in clinical trials and population-based investigations are also discussed. This review primarily delves into the antidiabetic potential and underlying mechanisms of tea active compounds, providing a theoretical basis for the practical application of tea and its active compounds against diabetes.

Diabetic kidney disease (DKD) is one of the chronic microvascular complications caused by diabetes, which is characterized by persistent albuminuria and/or progressive decline of estimated glomerular filtration rate (eGFR), and has been the major cause of dialysis around the world. At present, although the treatments for DKD including lifestyle modification, glycemic control and even using of Sodium-glucose cotransporter 2 (SGLT2) inhibitors can relieve kidney damage caused to a certain extent, there is still a lack of effective treatment schemes that can prevent DKD progressing to ESRD. It is urgent to find new complementary and effective therapeutic agents. Growing animal researches have shown that mitophagy makes a great difference to the pathogenesis of DKD, therefore, exploration of new drugs that target the restoration of mitophagy maybe a potential perspective treatment for DKD. The use of Chinese botanical drugs (CBD) has been identified to be an effective treatment option for DKD. There is growing concern on the molecular mechanism of CBD for treatment of DKD by regulating mitophagy. In this review, we highlight the current findings regarding the function of mitophagy in the pathological damages and progression of DKD and summarize the contributions of CBD that ameliorate renal injuries in DKD by interfering with mitophagy, which will help us further explain the mechanism of CBD in treatment for DKD and explore potential therapeutic strategies for DKD.

Abamectin (AB) is widely used in agriculture and has been employed as an insecticide, nematicide, and livestock pest control agent. However, it may also pose a serious threat to mammals. The primary purpose of this research was to compare the sex variations between male and female rats during exposure and to assess the risk of toxicity of abamectin, which are still largely unknown. The twenty albino rats were divided randomly into four groups (n = 5): 1) the male control group; 2) the male treatment group treated with AB (1 mg/kg B.W.); 3) the female control group; and 4) the female treatment group treated with AB (1 mg/kg B.W.). AB administration caused a drop in body weight in females more than males with showing oxidative stress in both sexes of animals, as characterized by an increase in MDA content and a decrease in glutathione (GSH) content and superoxide dismutase (SOD) activity. Reported sex-specific effects suggested that females are more susceptible from males in brain tissues for alteration of antioxidant markers while females' liver and kidney tissues showed more level of lipid peroxidation than males. In addition, mitochondrial dysfunction was associated with a significant decrease in NADH dehydrogenase (Complex I) and a significant decrease in mitochondrial ATPase, which led to apoptosis and histopathological alterations in the targeted tissues, indicating that females are higher sensitive than males to these biological events. In brief, the results of this study led to female rats are generally more sensitive than male rats to neurobehavioral and hepatic complications associated with abamectin treatment. Further evaluation should be performed to determine the adverse outcome pathways involved and to determine the effects of sex on improving the risk assessment of abamectin in both sexes.

Sirtuins (SIRTs) are putative regulators of lifespan in model organisms. Since the initial discovery that SIRTs could promote longevity in nematodes and flies, the identification of additional properties of these proteins has led to understanding of their roles as exquisite sensors that link metabolic activity to oxidative states. SIRTs have major roles in biological processes that are important in kidney development and physiological functions, including mitochondrial metabolism, oxidative stress, autophagy, DNA repair and inflammation. Furthermore, altered SIRT activity has been implicated in the pathophysiology and progression of acute and chronic kidney diseases, including acute kidney injury, diabetic kidney disease, chronic kidney disease, polycystic kidney disease, autoimmune diseases and renal ageing. The renoprotective roles of SIRTs in these diseases make them attractive therapeutic targets. A number of SIRT-activating compounds have shown beneficial effects in kidney disease models; however, further research is needed to identify novel SIRT-targeting strategies with the potential to treat and/or prevent the progression of kidney diseases and increase the average human healthspan.

Recent studies have highlighted that retinal neurodegeneration precedes microvascular changes in diabetic retinopathy (DR), but the specific mechanisms remain unclear. Given the pivotal role of dysfunctional mitochondria and oxidative stress in early DR, our objective was to observe mitochondria-related alterations in the neural retina of type one diabetic mellitus mice with no evidence of DR (T1DM-NDR). We aimed to identify the key mitochondrial-related proteins contributing to mitochondrial injury. Our study revealed that T1DM-NDR mice exhibited outer retina thinning, including the ellipsoid zone, inner segment, and outer segment. Additionally, there was an impaired amplitude of the b-wave in electroretinogram (ERG) and a disorganized arrangement of the photoreceptor layer. In both the retina of DM mice and high glucose (HG)-treated 661w cells, mitochondria appeared swollen and fragmented, with disrupted cristae, disorganized or shortened branches in the mitochondrial network, and decreased mitochondrial membrane potential. Among the mitochondrial-related proteins, dynamin-related protein 1 (Drp1) was upregulated, and the ratio of phosphorylated Drp1 protein at serine 616 (S616) and serine 637 (S637) sites significantly increased in the retina of DM mice. The administration of Mdivi-1 ameliorated high-glucose-induced dysfunctional mitochondria, thereby protecting T1DM-NDR mice retina from morphological and functional injuries. Our findings suggest that hyperglycemia promotes Drp1-mediated mitochondrial dysfunction, which may be a significant factor in the development of DR. The inhibition of high-glucose-induced mitochondrial fission emerges as a potential and innovative intervention strategy for preventing DR.

Diabetes is not solely a metabolic disorder but also involves inflammatory processes. The immune response it incites is a primary contributor to damage in target organs. Research indicates that during the initial phases of diabetic nephropathy, macrophages infiltrate the kidneys alongside lymphocytes, initiating a cascade of inflammatory reactions. The interplay between macrophages and other renal cells is pivotal in the advancement of kidney disease within a hyperglycemic milieu. While M1 macrophages react to the inflammatory stimuli induced by elevated glucose levels early in the disease progression, their subsequent transition to M2 macrophages, which possess anti-inflammatory and tissue repair properties, also contributes to fibrosis in the later stages of nephropathy by transforming into myofibroblasts. Comprehending the diverse functions of macrophages in diabetic kidney disease and regulating their activity could offer therapeutic benefits for managing this condition.

Endothelial dysfunction is a hallmark of cardiovascular diseases, contributing to impaired vasodilation, altered hemodynamics, and atherosclerosis progression. Trimetazidine, traditionally used for angina pectoris, exhibits diverse therapeutic effects on endothelial dysfunction. This review aims to elucidate the mechanisms underlying trimetazidine's actions and its potential as a therapeutic agent for endothelial dysfunction and associated cardiovascular disorders. Trimetazidine enhances vasodilation and hemodynamic function by modulating endothelial nitric oxide synthase activity, nitric oxide production, and endothelin-1. It also ameliorates metabolic parameters, including reducing blood glucose, mitigating oxidative stress, and dampening inflammation. Additionally, trimetazidine exerts antiatherosclerotic effects by inhibiting plaque formation and promoting its stability. Moreover, it regulates apoptosis and angiogenesis, fostering endothelial cell survival and neovascularization. Understanding trimetazidine's multifaceted mechanisms underscores its potential as a therapeutic agent for endothelial dysfunction and associated cardiovascular disorders, warranting further investigation for clinical translation.

Podocyte apoptosis exerts a crucial role in the pathogenesis of DN. Recently, long noncoding RNAs (lncRNAs) have been gradually identified to be functional in a variety of different mechanisms associated with podocyte apoptosis. This study aimed to investigate whether lncRNA Glis2 could regulate podocyte apoptosis in DN and uncover the underlying mechanism. The apoptosis rate was detected by flow cytometry. Mitochondrial membrane potential (ΔΨM) was measured using JC-1 staining. Mitochondrial morphology was detected by MitoTracker Deep Red staining. Then, the histopathological and ultrastructure changes of renal tissues in diabetic mice were observed using periodic acid-Schiff (PAS) staining and transmission electron microscopy. We found that lncRNA Glis2 was significantly downregulated in high-glucose cultured podocytes and renal tissues of db/db mice. LncRNA Glis2 overexpression was found to alleviate podocyte mitochondrial dysfunction and apoptosis. The direct interaction between lncRNA Glis2 and miR-328-5p was confirmed by dual luciferase reporter assay. Furthermore, lncRNA Glis2 overexpression alleviated podocyte apoptosis in diabetic mice. Taken together, this study demonstrated that lncRNA Glis2, acting as a competing endogenous RNA (ceRNA) of miRNA-328-5p, regulated Sirt1-mediated mitochondrial dysfunction and podocyte apoptosis in DN.

Osteoarthritis (OA) is the most common type of arthritis and is an age-related joint disease that is particularly prevalent in subjects over 65 years old. The chronic rise of senescent cells has a close correlation with age-related diseases such as OA, and the senescence-associated secretory phenotype (SASP) is implicated in OA cartilage degeneration pathogenesis. Sirtuin 6 (SIRT6) is likely to be a key senescence-related regulator. Fisetin (FST) is a natural flavonol of the flavonoid family that is recommended as a senolytic drug to extend health and lifespan. However, the potential chondroprotective effects of FST on OA rats are largely unclarified. The aim of this study is to investigate the ameliorative effects of FST on OA joint cartilage and the relationship with SIRT6 and the detailed mechanisms from anti-inflammatory and anti-senescent perspectives. Rats were subjected to destabilization of the medial meniscus (DMM) surgery as a means of inducing the experimental OA model in vivo. Chondrocytes treated with IL-1β were utilized for mimicking the OA cell model in vitro. Intra-articular injection of FST, OSS_128,167 (OSS, SIRT6 inhibitor), and MDL800 (MDL, SIRT6 agonist) in vivo or administering them in IL-1β-induced rat chondrocytes in vitro were performed in order to determine the effects FST has on OA and the link with SIRT6. This study found SIRT6 level to be negatively correlated with OA severity. SIRT6 downregulation was validated in the joint cartilages of DMM rats and IL-1β-treated chondrocytes. It was also notably demonstrated that FST can activate SIRT6. Both the administration of FST and activation of SIRT6 using MDL were found to rescue cartilage erosion, decrease extracellular matrix (ECM) degradation, prevent cartilage from apoptosis, and improve detrimental senescence-related phenotype. The alleviative effects of FST against inflammation, ECM degradation, apoptosis, and senescence in IL-1β-stimulated chondrocytes were also confirmed. SIRT6 loss occurs in articular cartilage in OA pathogenesis, which is linked to aging. FST attenuates injury-induced aging-related phenotype changes in chondrocytes through the targeting of SIRT6.

Sirtuins, which are NAD+-dependent class III histone deacetylases, are involved in various biological processes, including DNA damage repair, immune inflammation, oxidative stress, mitochondrial homeostasis, autophagy, and apoptosis. Sirtuins are essential regulators of cellular function and organismal health. Increasing evidence suggests that the development of age-related diseases, including kidney diseases, is associated with aberrant expression of sirtuins, and that regulation of sirtuins expression and activity can effectively improve kidney function and delay the progression of kidney disease. In this review, we summarise current studies highlighting the role of sirtuins in renal diseases. First, we discuss sirtuin family members and their main mechanisms of action. We then outline the possible roles of sirtuins in various cell types in kidney diseases. Finally, we summarise the compounds that activate or inhibit sirtuin activity and that consequently ameliorate renal diseases. In conclusion, targeted modulation of sirtuins is a potential therapeutic strategy for kidney diseases. Video Abstract.