Roles of Sirt1 and its modulators in diabetic microangiopathy: A review.

Diabetic vascular complications include diabetic macroangiopathy and diabetic microangiopathy. Diabetic microangiopathy is characterised by impaired microvascular endothelial function, basement membrane thickening, and microthrombosis, which may promote renal, ocular, cardiac, and peripheral system damage in diabetic patients. Therefore, new preventive and therapeutic strategies are urgently required. Sirt1, a member of the nicotinamide adenine dinucleotide-dependent histone deacetylase class III family, regulates different organ growth and development, oxidative stress, mitochondrial function, metabolism, inflammation, and aging. Sirt1 is downregulated in vascular injury and microangiopathy. Moreover, its expression and distribution in different organs correlate with age and play critical regulatory roles in oxidative stress and inflammation. This review introduces the background of diabetic microangiopathy and the main functions of Sirt1. Then, the relationship between Sirt1 and different diabetic microangiopathies and the regulatory roles mediated by different cells are described. Finally, we summarize the modulators that target Sirt1 to ameliorate diabetic microangiopathy as an essential preventive and therapeutic measure for diabetic microangiopathy. In conclusion, targeting Sirt1 may be a new therapeutic strategy for diabetic microangiopathy.

Exploring the tumor microenvironment: Chemokine-related genes and immunotherapy/chemotherapy response in clear-cell renal cell carcinoma.

BACKGROUND: The treatment of clear-cell renal cell carcinoma (ccRCC) remains challenge. Chemokines laid impact on the proliferation and metastasis of cancer cells. The objective was to identify the chemokine-related genes and construct a prognostic model for ccRCC. METHODS: Bulk transcriptomic data (n = 531), single-cell RNA sequencing (scRNA-seq) dataset GSE159115, and other validation cohorts were acquired from the Cancer Genome Atlas Program (TCGA) and GEO databases. All clustering analysis was conducted by Seurat R package. Gene set enrichment analysis (GSEA), immune infiltration analysis, single nucleotide variations (SNV) analysis, and predictive response analysis of immunotherapy/chemotherapy were conducted. 786-O and A498 cell lines were cultured and applied into CCK-8, Western blot, and RT-qPCR kits. RESULTS: Univariate Cox analysis was used to screen out chemokine-related genes related to survival. ZIC2, SMIM24, COL7A1, IGF2BP3, ITPKA, ADAMTS14, CYP3A7, and AURKB were identified and applied for the construction of the prognostic model. High-risk group had a poorer prognosis than the low-risk group in each dataset. Memory CD8+ T cells, macrophages, and memory B cells were higher in the high-risk group, while the content of basophils was higher in the low-risk group. Bortezomib_1191, Dactinomycin_1911, Docetaxel_1007, and Daporinad_1248 were more sensitive to high-risk groups than low-risk groups. Moreover, we found that IGF2BP3 significantly elevated in both 786-O and A498 cell lines resistance to sunitinib. Knockdown of IGF2BP3 markedly reduced ccRCC cell migration and viability. CONCLUSION: Our study has yielded a novel prognostic model of chemokine-related genes based on comprehensive transcriptional atlas of ccRCC patients, shedding light on the significant impact of the tumor microenvironment on biology and immunotherapy response of ccRCC. We identified IGF2BP3 as a pivotal regulator in regulating ccRCC resistance to sunitinib.

Serum high mobility group box 1 as a potential biomarker for the progression of kidney disease in patients with type 2 diabetes.

Background: As a damage-associated molecular pattern protein, high mobility group box 1 (HMGB1) is associated with kidney and systemic inflammation. The predictive and therapeutic value of HMGB1 as a biomarker has been confirmed in various diseases. However, its value in diabetic kidney disease (DKD) remains unclear. Therefore, this study aimed to investigate the correlation between serum and urine HMGB1 levels and DKD progression. Methods: We recruited 196 patients with type 2 diabetes mellitus (T2DM), including 109 with DKD and 87 T2DM patients without DKD. Additionally, 60 healthy participants without T2DM were also recruited as controls. Serum and urine samples were collected for HMGB1 analysis. Simultaneously, tumor necrosis factor receptor superfamily member 1A (TNFR-1) in serum and kidney injury molecule (KIM-1) in urine samples were evaluated for comparison. Results: Serum and urine HMGB1 levels were significantly higher in patients with DKD than in patients with T2DM and healthy controls. Additionally, serum HMGB1 levels significantly and positively correlated with serum TNFR-1 (R 2 = 0.567, p<0.001) and urine KIM-1 levels (R 2 = 0.440, p<0.001), and urine HMGB1 has a similar correlation. In the population with T2DM, the risk of DKD progression increased with an increase in serum HMGB1 levels. Multivariate logistic regression analysis showed that elevated serum HMGB1 level was an independent risk factor for renal function progression in patients with DKD, and regression analysis did not change in the model corrected for multiple variables. The restricted cubic spline depicted a nonlinear relationship between serum HMGB1 and renal function progression in patients with DKD (p-nonlinear=0.007, p<0.001), and this positive effect remained consistent across subgroups. Conclusion: Serum HMGB1 was significantly correlated with DKD and disease severity. When the HMGB1 level was ≥27 ng/ml, the risk of renal progression increased sharply, indicating that serum HMGB1 can be used as a potential biomarker for the diagnosis of DKD progression.

Sirtuins in kidney diseases: potential mechanism and therapeutic targets.

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.

Tangshen formula protects against podocyte apoptosis via enhancing the TFEB-mediated autophagy-lysosome pathway in diabetic nephropathy.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease and currently there are no specific and effective drugs for its treatment. Podocyte injury is a detrimental feature and the major cause of albuminuria in DN. We previously reported Tangshen Formula (TSF), a Chinese herbal medicine, has shown therapeutic effects on DN. However, the underlying mechanisms remain obscure. AIM OF THE STUDY: This study aimed to explore the protective effect of TSF on podocyte apoptosis in DN and elucidate the potential mechanism. MATERIALS AND METHODS: The effects of TSF were assessed in a murine model using male KKAy diabetic mice, as well as in advanced glycation end products-stimulated primary mice podocytes. Transcription factor EB (TFEB) knockdown primary podocytes were employed for mechanistic studies. In vivo and in vitro studies were performed and results assessed using transmission electron microscopy, immunofluorescence staining, and western blotting. RESULTS: TSF treatment alleviated podocyte apoptosis and structural impairment, decreased albuminuria, and mitigated renal dysfunction in KKAy mice. Notably, TSF extracted twice showed a more significant reduction in proteinuria than TSF extracted three times. Accumulation of autophagic biomarkers p62 and LC3, and aberrant autophagic flux in podocytes of DN mice were significantly altered by TSF therapy. Consistent with the in vivo results, TSF prevented the apoptosis of primary podocytes exposed to AGEs and activated autophagy. However, the anti-apoptosis capacity of TSF was countered by the autophagy-lysosome inhibitor chloroquine. We found that TSF increased the nuclear translocation of TFEB in diabetic podocytes, and thus upregulated transcription of its several autophagic target genes. Pharmacological activation of TFEB by TSF accelerated the conversion of autophagosome to autolysosome and lysosomal biogenesis, further augmented autophagic flux. Conversely, TFEB knockdown negated the favorable effects of TSF on autophagy in AGEs-stimulated primary podocytes. CONCLUSIONS: These findings indicate TSF appears to attenuate podocyte apoptosis and promote autophagy in DN via the TFEB-mediated autophagy-lysosome system. Thus, TSF may be a therapeutic candidate for DN.

Knowledge landscapes and emerging trends of cardiorenal syndrome type 4: a bibliometrics and visual analysis from 2004 to 2022.

PURPOSE: To evaluate the key topics and emerging trends in the field of cardiorenal syndrome type 4 (CRS-4) by bibliometrics and visual analysis. METHODS: Citespace, VOSviewer, and Bibliometrix package were used to analyze the collected data from the Web of Science Core Collection, including publication trends, leading countries, active authors and institutions, co-cited references, journals, and keyword analysis. RESULTS: Finally, 2267 articles were obtained. From 2004 to 2022, the number of publications was increasing year by year. A total of 735 authors from 543 institutions in 94 countries/regions participated in the publication of CRS-4 field, which were mostly from North America and Europe. Most of the co-cited references were reviews or guidelines from kidney/heart specialist journals or top journals. The journals concerning nephrology had a higher academic influence in this field. Oxidative stress and inflammation remained hot topics in CRS-4 research, as well as uremic toxins. Fibroblast growth factor 23 and klotho were emerging trends in recent years. Sodium glucose cotransporter 2 (SGLT2) inhibitors were the latest frontier hot spots. Future research advances may pay more attention to the prevention and prognosis assessment of CRS-4. CONCLUSION: Our study provides some key information for scholars to determine the direction of future research.

Genetic evidence supporting the causal role of gut microbiota in chronic kidney disease and chronic systemic inflammation in CKD: a bilateral two-sample Mendelian randomization study.

Background: The association of gut microbiota (GM) and chronic kidney disease (CKD), and the relevancy of GM and chronic systemic inflammation in CKD, were revealed on the basis of researches on gut-kidney axis in previous studies. However, their causal relationships are still unclear. Objective: To uncover the causal relationships between GM and CKD, as well as all known GM from eligible statistics and chronic systemic inflammation in CKD, we performed two-sample Mendelian randomization (MR) analysis. Materials and methods: We acquired the latest and most comprehensive summary statistics of genome-wide association study (GWAS) from the published materials of GWAS involving GM, CKD, estimated glomerular filtration rate (eGFR), c-reactive protein (CRP) and urine albumin creatine ratio (UACR). Subsequently, two-sample MR analysis using the inverse-variance weighted (IVW) method was used to determine the causality of exposure and outcome. Based on it, additional analysis and sensitivity analysis verified the significant results, and the possibility of reverse causality was also assessed by reverse MR analysis during this study. Results: At the locus-wide significance threshold, IVW method and additional analysis suggested that the protective factors for CKD included family Lachnospiraceae (P=0.049), genus Eubacterium eligens group (P=0.002), genus Intestinimonas (P=0.009), genus Streptococcu (P=0.003) and order Desulfovibrionales (P=0.001). Simultaneously, results showed that genus LachnospiraceaeUCG010 (P=0.029) was a risk factor for CKD. Higher abundance of genus Desulfovibrio (P=0.048) was correlated with higher eGFR; higher abundance of genus Parasutterella (P=0.018) was correlated with higher UACR; higher abundance of class Negativicutes (P=0.003), genus Eisenbergiella (P=0.021), order Selenomonadales (P=0.003) were correlated with higher CRP levels; higher abundance of class Mollicutes (0.024), family Prevotellaceae (P=0.030), phylum Tenericutes (P=0.024) were correlated with lower levels of CRP. No significant pleiotropy or heterogeneity was found in the results of sensitivity analysis, and no significant causality was found in reverse MR analysis. Conclusion: This study highlighted associations within gut-kidney axis, and the causal relationships between GM and CKD, as well as GM and chronic systemic inflammation in CKD were also revealed. Meanwhile, we expanded specific causal gut microbiota through comprehensive searches. With further studies for causal gut microbiota, they may have the potential to be new biomarkers for targeted prevention of CKD and chronic systemic inflammation in CKD.

Targeting HMGB1: A Potential Therapeutic Strategy for Chronic Kidney Disease.

High-mobility group protein box 1 (HMGB1) is a member of a highly conserved high-mobility group protein present in all cell types. HMGB1 plays multiple roles both inside and outside the cell, depending on its subcellular localization, context, and post-translational modifications. HMGB1 is also associated with the progression of various diseases. Particularly, HMGB1 plays a critical role in CKD progression and prognosis. HMGB1 participates in multiple key events in CKD progression by activating downstream signals, including renal inflammation, the onset of persistent fibrosis, renal aging, AKI-to-CKD transition, and important cardiovascular complications. More importantly, HMGB1 plays a distinct role in the chronic pathophysiology of kidney disease, which differs from that in acute lesions. This review describes the regulatory role of HMGB1 in renal homeostasis and summarizes how HMGB1 affects CKD progression and prognosis. Finally, some promising therapeutic strategies for the targeted inhibition of HMGB1 in improving CKD are summarized. Although the application of HMGB1 as a therapeutic target in CKD faces some challenges, a more in-depth understanding of the intracellular and extracellular regulatory mechanisms of HMGB1 that underly the occurrence and progression of CKD might render HMGB1 an attractive therapeutic target for CKD.

Proteome-wide mendelian randomization study implicates therapeutic targets in common cancers.

BACKGROUND: The interest in targeted cancer therapies has been growing rapidly. While numerous cancer biomarkers and targeted treatment strategies have been developed and employed, there are still significant limitations and challenges in the early diagnosis and targeted treatment of cancers. Accordingly, there is an urgent need to identify novel targets and develop new targeted drugs. METHODS: The study was conducted using combined cis-Mendelian randomization (cis-MR) and colocalization analysis. We analyzed data from 732 plasma proteins to identify potential drug targets associated with eight site-specific cancers. These findings were further validated using the UK Biobank dataset. Then, a protein-protein interaction network was also constructed to examine the interplay between the identified proteins and the targets of existing cancer medications. RESULTS: This MR analysis revealed associations between five plasma proteins and prostate cancer, five with breast cancer, and three with lung cancer. Subsequently, these proteins were classified into four distinct target groups, with a focus on tier 1 and 2 targets due to their higher potential to become drug targets. Our study indicatied that genetically predicted KDELC2 (OR: 0.89, 95% CI 0.86-0.93) and TNFRSF10B (OR: 0.74, 95% CI 0.65-0.83) are inversely associated with prostate cancer. Furthermore, we observed an inverse association between CPNE1 (OR: 0.96, 95% CI 0.94-0.98) and breast cancer, while PDIA3 (OR: 1.19, 95% CI 1.10-1.30) were found to be associated with the risk of breast cancer. In addition, we also propose that SPINT2 (OR: 1.05, 95% CI 1.03-1.06), GSTP1 (OR: 0.82, 95% CI 0.74-0.90), and CTSS (OR: 0.91, 95% CI 0.88-0.95) may serve as potential therapeutic targets in prostate cancer. Similarly, GDI2 (OR: 0.85, 95% CI 0.80-0.91), ISLR2 (OR: 0.87, 95% CI 0.82-0.93), and CTSF (OR: 1.14, 95% CI 1.08-1.21) could potentially be targets for breast cancer. Additionally, we identified SFTPB (OR: 0.93, 95% CI 0.91-0.95), ICAM5 (OR: 0.95, 95% CI 0.93-0.97), and FLRT3 (OR: 1.10, 95% CI 1.05-1.15) as potential targets for lung cancer. Notably, TNFRSF10B, GSTP1, and PDIA3 were found to interact with the target proteins of current medications used in prostate or breast cancer treatment. CONCLUSIONS: This comprehensive analysis has highlighted thirteen plasma proteins with potential roles in three site-specific cancers. Continued research in this area may reveal their therapeutic potential, particularly KDELC2, TNFRSF10B, CPNE1, and PDIA3, paving the way for more effective cancer treatments.

Therapeutic application of traditional Chinese medicine in kidney disease: Sirtuins as potential targets.

Sirtuins are a family of NAD+ III-dependent histone deacetylases that consists of seven family members, Sirt1-Sirt7, which regulate various signalling pathways and are involved in many critical biological processes of kidney diseases. Traditional Chinese medicine (TCM), as an essential part of the global healthcare system, has multi-component and multi-pathway therapeutic characteristics and plays a role in preventing and controlling various diseases. Through ongoing collaboration with modern medicine, TCM has recently achieved many remarkable advancements in theoretical investigation, mechanistic research, and clinical applications related to kidney diseases. Therefore, a comprehensive and systematic summary of TCM that focuses on sirtuins as the intervention target for kidney diseases is necessary. This review introduces the relationship between abnormal sirtuins levels and common kidney diseases, such as diabetic kidney disease and acute kidney injury. Based on the standard biological processes, such as inflammation, oxidative stress, autophagy, mitochondrial homeostasis, and fibrosis, which are underlying kidney diseases, comprehensively describes the roles and regulatory effects of TCM targeting the sirtuins family in various kidney diseases.

Regulation of autophagy by natural polyphenols in the treatment of diabetic kidney disease: therapeutic potential and mechanism.

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes and a leading cause of end-stage renal disease worldwide. Autophagy plays an important role in maintaining cellular homeostasis in renal physiology. In DKD, the accumulation of advanced glycation end products induces decreased renal autophagy-related protein expression and transcription factor EB (TFEB) nuclear transfer, leading to impaired autophagy and lysosomal function and blockage of autophagic flux. This accelerates renal resident cell injury and apoptosis, mediates macrophage infiltration and phenotypic changes, ultimately leading to aggravated proteinuria and fibrosis in DKD. Natural polyphenols show promise in treating DKD by regulating autophagy and promoting nuclear transfer of TFEB and lysosomal repair. This review summarizes the characteristics of autophagy in DKD, and the potential application and mechanisms of some known natural polyphenols as autophagy regulators in DKD, with the goal of contributing to a deeper understanding of natural polyphenol mechanisms in the treatment of DKD and promoting the development of their applications. Finally, we point out the limitations of polyphenols in current DKD research and provide an outlook for their future research.

Oxidative stress and inflammation in diabetic nephropathy: role of polyphenols.

Diabetic nephropathy (DN) often leads to end-stage renal disease. Oxidative stress demonstrates a crucial act in the onset and progression of DN, which triggers various pathological processes while promoting the activation of inflammation and forming a vicious oxidative stress-inflammation cycle that induces podocyte injury, extracellular matrix accumulation, glomerulosclerosis, epithelial-mesenchymal transition, renal tubular atrophy, and proteinuria. Conventional treatments for DN have limited efficacy. Polyphenols, as antioxidants, are widely used in DN with multiple targets and fewer adverse effects. This review reveals the oxidative stress and oxidative stress-associated inflammation in DN that led to pathological damage to renal cells, including podocytes, endothelial cells, mesangial cells, and renal tubular epithelial cells. It demonstrates the potent antioxidant and anti-inflammatory properties by targeting Nrf2, SIRT1, HMGB1, NF-κB, and NLRP3 of polyphenols, including quercetin, resveratrol, curcumin, and phenolic acid. However, there remains a long way to a comprehensive understanding of molecular mechanisms and applications for the clinical therapy of polyphenols.

Causal effects between gut microbiota and IgA nephropathy: a bidirectional Mendelian randomization study.

Background: Therapeutic approaches that target the gut microbiota (GM) may be helpful in the potential prevention and treatment of IgA nephropathy (IgAN). Meanwhile, relevant studies demonstrated a correlation between GM and IgAN, however, these confounding evidence cannot prove a causal relationship between GM and IgAN. Methods: Based on the data from the GM genome-wide association study (GWAS) of MiBioGen and the IgAN GWAS data from the FinnGen research. A bi-directional Mendelian randomization (MR) study was performed to explore the causal relationship between GM and IgAN. We used inverse variance weighted (IVW) method as the primary method to determine the causal relationship between exposure and outcome in our MR study. Besides, we used additional analysis (MR-Egger, weighted median) and sensitivity analysis (Cochrane's Q test, MR-Egger and MR-PRESSO) to select significant results, followed by Bayesian model averaging (MR-BMA) to test the results of MR study. Finally, a reverse MR analysis was conducted to estimate the probability of reverse causality. Results: At the locus-wide significance level, the results of IVW method and additional analysis showed that Genus Enterorhabdus was a protective factor for IgAN [OR: 0.456, 95% CI: 0.238-0.875, p=0.023], while Genus butyricicoccus was a risk factor for IgAN [OR: 3.471, 95% CI: 1.671-7.209, p=0.0008]. In the sensitivity analysis, no significant pleiotropy or heterogeneity of the results was found. Conclusion: Our study revealed the causal relationship between GM and IgAN, and expanded the variety of bacterial taxa causally related to IgAN. These bacterial taxa could become novel biomarkers to facilitate the development of targeted therapies for IgAN, developing our understanding of the "gut-kidney axis".

Therapeutic potential of artemisinin and its derivatives in managing kidney diseases.

Artemisinin, an antimalarial traditional Chinese herb, is isolated from Artemisia annua. L, and has shown fewer side effects. Several pieces of evidence have demonstrated that artemisinin and its derivatives exhibited therapeutic effects on diseases like malaria, cancer, immune disorders, and inflammatory diseases. Additionally, the antimalarial drugs demonstrated antioxidant and anti-inflammatory activities, regulating the immune system and autophagy and modulating glycolipid metabolism properties, suggesting an alternative for managing kidney disease. This review assessed the pharmacological activities of artemisinin. It summarized the critical outcomes and probable mechanism of artemisinins in treating kidney diseases, including inflammatory, oxidative stress, autophagy, mitochondrial homeostasis, endoplasmic reticulum stress, glycolipid metabolism, insulin resistance, diabetic nephropathy, lupus nephritis, membranous nephropathy, IgA nephropathy, and acute kidney injury, suggesting the therapeutic potential of artemisinin and its derivatives in managing kidney diseases, especially the podocyte-associated kidney diseases.

Comprehensive bibliometric analysis of sirtuins: Focus on sirt1 and kidney disease.

Sirtuins, as regulators of metabolism and energy, have been found to play an important role in health and disease. Sirt1, the most widely studied member of the sirtuin family, can ameliorate oxidative stress, immune inflammation, autophagy, and mitochondrial homeostasis by deacetylating regulatory histone and nonhistone proteins. Notably, sirt1 has gradually gained attention in kidney disease research. Therefore, an evaluation of the overall distribution of publications concerning sirt1 based on bibliometric analysis methods to understand the thematic evolution and emerging research trends is necessary to discover topics with potential implications for kidney disease research. We conducted a bibliometric analysis of publications derived from the Web of Science Core Collection and found that publications concerning sirt1 have grown dramatically over the past 2 decades, especially in the past 5 years. Among these, the proportion of publications regarding kidney diseases have increased annually. China and the United States are major contributors to the study of sirt1, and Japanese researchers have made important contributions to the study of sirt1 in kidney disease. Obesity, and Alzheimer's disease are hotspots diseases for the study of sirt1, while diabetic nephropathy is regarded as a research hotspot in the study of sirt1 in kidney disease. NAD+, oxidative stress, and p53 are the focus of the sirt1 research field. Autophagy and NLRP3 inflammasome are emerging research trends have gradually attracted the interest of scholars in sirt1, as well as in kidney disease. Notably, we also identified several potential research topics that may link sirt1 and kidney disease, which require further study, including immune function, metabolic reprogramming, and fecal microbiota.

Potential therapeutic effects of natural compounds targeting autophagy to alleviate podocyte injury in glomerular diseases.

Podocyte injury is a common cause of proteinuric kidney diseases. Uncontrollable progressive podocyte loss accelerates glomerulosclerosis and increases the risk of end-stage renal disease. To date, owing to the complex pathological mechanism, effective therapies for podocyte injury have been limited. Accumulating evidence supports the indispensable role of autophagy in the maintenance of podocyte homeostasis. A variety of natural compounds and their derivatives have been found to regulate autophagy through multiple targets, including promotes nuclear transfer of transcription factor EB and lysosomal repair. Here, we reviewed the recent studies on the use of natural compounds and their derivatives as autophagy regulators and discussed their potential applications in ameliorating podocyte injury. Several known natural compounds with autophagy-regulatory properties, such as quercetin, silibinin, kaempferol, and artemisinin, and their medical uses were also discussed. This review will help in improving the understanding of the podocyte protective mechanism of natural compounds and promote their development for clinical use.

Sirtuins as novel pharmacological targets in podocyte injury and related glomerular diseases.

Podocyte injury is a major cause of proteinuria in kidney diseases, and persistent loss of podocytes leads to rapid irreversible progression of kidney disease. Sirtuins, a class of nicotinamide adenine dinucleotide-dependent deacetylases, can promote DNA repair, modify transcription factors, and regulate the cell cycle. Additionally, sirtuins play a critical role in renoprotection, particularly against podocyte injury. They also have pleiotropic protective effects on podocyte injury-related glomerular diseases, such as improving the immune inflammatory status and oxidative stress levels, maintaining mitochondrial homeostasis, enhancing autophagy, and regulating lipid metabolism. Sirtuins deficiency causes podocyte injury in different glomerular diseases. Studies using podocyte sirtuin-specific knockout and transgenic models corroborate this conclusion. Of note, sirtuin activators have protective effects in different podocyte injury-related glomerular diseases, including diabetic kidney disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, and lupus nephritis. These findings suggest that sirtuins are promising therapeutic targets for preventing podocyte injury. This review provides an overview of recent advances in the role of sirtuins in kidney diseases, especially their role in podocyte injury, and summarizes the possible rationale for sirtuins as targets for pharmacological intervention in podocyte injury-related glomerular diseases.

Cardioprotection effect of Yiqi-Huoxue-Jiangzhuo formula in a chronic kidney disease mouse model associated with gut microbiota modulation and NLRP3 inflammasome inhibition.

BACKGROUND: The pathogenesis and treatment of cardiovascular disease mediated by chronic kidney disease (CKD) are key research questions. Specifically, the mechanisms underlying the cardiorenal protective effect of Yiqi-Huoxue-Jiangzhuo formula (YHJF), a traditional Chinese herbal medicine, have not yet been clarified. METHODS: A classical CKD mouse model was constructed by 5/6 nephrectomy (Nx) to study the effects of YHJF intervention on 5/6 Nx mice cardiorenal function, gut microbial composition, gut-derived metabolites, and NLRP3 inflammasome pathways. RESULTS: YHJF improved cardiac dysfunction and reversed left ventricular hypertrophy, myocardial hypertrophy, and interstitial fibrosis in 5/6 Nx mice. In addition, YHJF inhibited activation of the NLRP3 inflammasome and downregulated the expression of TNF-α and IL-1ß both in the heart and serum; reconstitution of the intestinal flora imbalance was also found in 5/6 Nx mice treated with YHJF. Spearman's correlation and redundancy analyses showed that changes in the intestinal flora of 5/6 Nx mice were related to clinical phenotype and serum inflammatory levels. CONCLUSIONS: Treatment with YHJF effectively protected the heart function of 5/6 Nx mice; this effect was attributed to inhibition of NLRP3 inflammasome activation and regulation of intestinal microbial composition and derived metabolites. YHJF has potential for improving intestinal flora imbalance and gut-derived toxin accumulation in patients with CKD, thereby preventing cardiovascular complications.

Efficacy and safety of Abelmoschus manihot in treating chronic kidney diseases: A multicentre, open-label and single-arm clinical trial.

RATIONALE AND OBJECTIVE: The efficacy of Abelmoschus manihot (AM) in treating of chronic kidney disease (CKD) has been confirmed by prior trials. AM is also commonly combined to other medicines among CKD patients in clinic. This trial aimed at evaluating the safety of AM combination application, and further verifying the efficacy of AM in treating various types of CKD. STUDY DESIGN: A multicentre, prospective, open-label, single-arm trial SETTING AND PARTICIPANTS: Approximately 2000 CKD patients with proteinuria (≥ 150 mg/d), from 105 centres across China INTERVENTIONS: AM was administered to patients three times per day for 24 weeks: the daily dose was based on age (> 12 years old: 2.5 g tid; 6∼12 years old: 1.5 g tid; 2∼6 years old: 1 g tid) OUTCOMES: The efficacy outcomes were the change in 24-hour proteinuria and estimated glomerular filtration rate (eGFR) from baseline to week 24. Safety outcomes included adverse events and laboratory tests. RESULTS: 2054 CKD patients from 105 centres were enrolled in this trial, with 1843 (89.7%) completing the 24-week follow-up. The participants' median age was 44 years old and 44.6% were female. Compared to baseline, 24-hour proteinuria decreased 471 mg (95% confident interval, 367 to 575, p < 0.001) at week 24. eGFR did not change significantly relative to baseline with the mean increase as 1.7 ml/min/1.73 m2 (95% confident interval, -0.3 to 3.7, p = 0.09). 902 (43.9%) participants combined medication to AM during follow-up. The total incidence of adverse events was 12.9%; and the most common adverse events were hyperlipidaemia (4.1%), abnormal liver function (2.3%), upper respiratory infection (1.8%), and hyperglycaemia (1.1%). Combined medications did not change the risk for hyperlipidaemia and upper respiratory infection. The combination application with antiplatelet reagents increased the risk of abnormal liver function, and with calcium channel blockers increased the risk of hyperglycaemia. LIMITATIONS: Single-arm clinical trial and short observation time CONCLUSION: We have provided safety information of AM on various types of CKD in a large trial, especially when combination to medications most commonly prescribed to CKD patients. AM also showed to decrease proteinuria with stable kidney function during follow up. AM is a promising treatment for CKD patients.

Knowledge Domain and Emerging Trends in Podocyte Injury Research From 1994 to 2021: A Bibliometric and Visualized Analysis.

Background: Podocyte injury has a direct causal relationship with proteinuria and glomerulosclerosis and, on a chronic level, can lead to irreversible disease progression. Podocyte injury plays a critically decisive role in the development of proteinuric kidney disease. In recent years, the research on podocyte injury has developed rapidly all over the world. However, no report has summarized the field of podocyte injury as a whole to date. Using bibliometric analysis, this study aimed to evaluate the current state of worldwide podocyte injury research in the last 30 years and identify important achievements, primary research fields, and emerging trends. Methods: Publications related to podocyte injury were retrieved from Web of Science Core Collection. HistCite, VOSviewer, CiteSpace, and the Bibliometrix Package were used for bibliometric analysis and visualization, including the analysis of the overall distribution of annual outputs, leading countries, active institutions and authors, core journals, co-cited references, and keywords. Total global citation score and total local citation score were used to assess the quality and impact of publications. Results: A total of 2,669 publications related to podocyte injury were identified. Publications related to podocyte injury tended to increase continuously. A total of 10,328 authors from 2,171 institutions in 69 countries published studies related to podocyte injury. China (39.46%) was the most prolific country, and the number of citations of studies in the United States (cited 36,896 times) ranked first. Moin A Saleem, John Cijiang He, and Zhihong Liu were the top three contributing authors, and Journal of the American Society of Nephrology and Kidney International were the most popular journals in the field. "Diabetic nephropathy" is the primary focus area of podocyte injury research, and "autophagy," "microRNA," and "inflammation" were the top keywords of emerging research hotspots, and traditional Chinese medicine monomer may be a neglected research gap. Conclusion: Our research found that global publications on podocyte injury have increased dramatically. Diabetic nephropathy is the main research field of podocyte injury, whereas autophagy, microRNA, and inflammation are the top topics getting current attention from scholars and which may become the next focus in podocyte injury research.