Treatment Of Diabetic Kidney Disease Research Articles

Human placenta-derived mesenchymal stem cells ameliorate diabetic kidney disease by modulating the T helper 17 cell/ regulatory T-cell balance through the programmed death 1 / programmed death-ligand 1 pathway.

To investigate the therapeutic effects and immunomodulatory mechanisms of human placenta-derived mesenchymal stem cells (PMSCs) in diabetic kidney disease (DKD). Streptozotocin-induced DKD rats were administered an equivalent volume of saline or PMSCs (1 × 106 in 2 mL phosphate-buffered saline per rat) for 3 weeks. Eight weeks after treatment, we examined the biochemical parameters in the blood and urine, the ratio of T helper 17 cells (Th17) and regulatory T cells (Treg) in the blood, cytokine levels in the kidney and blood, and renal histopathological changes. In addition, we performed PMSC tracing and renal transcriptomic analyses using RNA-sequencing. Finally, we determined whether PMSCs modulated the Th17/Treg balance by upregulating programmed death 1 (PD-1) in vitro. The PMSCs significantly improved renal function, which was assessed by serum creatinine levels, urea nitrogen, cystatin C levels, urinary albumin-creatinine ratio, and the kidney index. Further, PMSCs alleviated pathological changes, including tubular vacuolar degeneration, mesangial matrix expansion, and glomerular filtration barrier injury. In the DKD rats in our study, PMSCs were mainly recruited to immune organs, rather than to the kidney or pancreas. PMSCs markedly promoted the Th17/Treg balance and reduced the levels of pro-inflammatory cytokines (interleukin [IL]-17A and IL-1β) in the kidney and blood of DKD rats. In vitro experiments showed that PMSCs significantly reduced the proportion of Th17 cells and increased the proportion of Treg cells by upregulating PD-1 in a cell-cell contact manner and downregulating programmed death-ligand 1 (PD-L1) expression in PMSCs, which reversed the Th17/Treg balance. We found that PMSCs improved renal function and pathological damage in DKD rats and modulated Th17/Treg balance through the PD-1/PD-L1 pathway. These findings provide a novel mechanism and basis for the clinical use of PMSCs in the treatment of DKD.

Active role of amino acid metabolism in early diagnosis and treatment of diabetic kidney disease.

Diabetic Kidney Disease (DKD) is one of the significant microvascular consequences of type 2 diabetes mellitus with a complex etiology and protracted course. In the early stages of DKD, the majority of patients experience an insidious onset and few overt clinical symptoms and indicators, but they are prone to develop end-stage renal disease in the later stage, which is life-threatening. The abnormal amino acid metabolism is tightly associated with the development of DKD, which involves several pathological processes such as oxidative stress, inflammatory response, and immune response and is also closely related to autophagy, mitochondrial dysfunction, and iron death. With a focus on taurine, branched-chain amino acids (BCAAs) and glutamine, we explored the biological effects of various amino acid mechanisms linked to DKD, the impact of amino acid metabolism in the early diagnosis of DKD, and the role of amino acid metabolism in treating DKD, to offer fresh objectives and guidelines for later early detection and DKD therapy.

Effects of liraglutide on extraglycemic inflammatory markers and renal hemodynamic parameters in diabetic kidney disease (DKD).

Diabetic kidney disease (DKD) was the leading cause of kidney disease, which has been a crucial public health. Liraglutide is a drug, widely used for DKD treatment globally. However, the extraglycemic inflammatory markers and renal hemodynamic parameters of DKD patients treated with liraglutide has been not reported. In this study, 160 patients with early DKD were enrolled, 80 cases in the control group and 80 cases in the treatment group, respectively. The individuals in the control group were treated with metformin, while the individuals in the treatment group were treated with liraglutide and metformin for 3 months. The urinary microalbumin and urinary creatinine was measured to calculate the ratio (UACR), while the Doppler ultrasound were measured before and after treatment. After 3 months of treatment, body mass index (BMI), waist circumference (WC) and low-density lipoprotein cholesterol (LDL) in the treatment group were significantly decreased compared with before and after treatment in the control group; the levels of cystatin and UACR in treatment group were lower than before treatment and control group; The end-diastolic blood flow velocity (EDV) of renal artery and segment artery in treatment group was significantly higher than that before treatment and control group; The levels of CRP, TNF-α and IL-6 in the treatment group after treatment were lower than those before treatment and those in the control group. After 3 months of treatment, blood cystatin in the treatment group decreased significantly compared with before treatment and after treatment in the control group, with statistical significance After 3 months of treatment, the EDV of renal artery and renal segment in treatment group was significantly higher than that before treatment and control group, the peak systolic blood flow velocity (PSV) and EDV of renal interlobar artery in treatment group were significantly higher than those before treatment and control group. The resistance index (RI) was significantly lower than that before treatment and control group. Liraglutide can reduce inflammatory indicators, renal artery blood flow and renal function indicators in early DKD patients.

Effects of Niaoduqing granules on inflammatory response of diabetic kidney disease: A meta‑analysis.

Diabetic kidney disease (DKD) is one of the most severe chronic microvascular complications of diabetes and the leading cause of end-stage kidney disease worldwide. The mechanism of inflammation underlying DKD has been attracting attention over recent years, but effective therapeutic strategies have remained elusive. Niaoduqing (NDQ) granules are one of the most commonly used drugs for the treatment of DKD in China, and it has therapeutic effects against inflammation in DKD. Therefore, the aim of the present analysis was to evaluate the inflammatory response outcomes and safety of NDQ granules for the treatment of DKD. The following databases were searched from their inception to 31st of May 2023 to obtain published accounts of relevant randomized controlled trials: China National Knowledge Infrastructure, China Science and Technology Journal, Wanfang, The Chinese Biomedicine, PubMed, Web of Science and Cochrane Library. The 'risk of bias' evaluation tool produced by the Cochrane Collaboration Handbook was used for evaluating the quality, whereas Revman software (version 5.3) was used for meta-analysis. In total, 16 studies were included into the present study according to criteria, with a total of 1,526 patients. Compared with those in the control group, the results of the meta-analysis revealed that the combination of conventional treatment and NDQ granules may further decrease C-reactive protein [standardized mean difference (SMD), -1.33; 95% confidence interval (CI), -1.76, -0.91; P<0.00001], TNF-α (SMD, -1.90; 95% CI, -2.35,-1.45; P<0.00001) and IL-6 (SMD, -1.72; 95% CI, -2.52,-0.91; P<0.0001) levels, whilst increasing the clinical effective rate (risk ratio, 1.22; 95% CI, 1.14,1.29; P<0.00001), in patients with DKD. In terms of safety, a total of 34 and 39 patients included in the intervention and in the control group, respectively, developed adverse reactions. Results from the present analysis suggest that NDQ granules may be beneficial in suppressing inflammation caused by DKD when used in combination with conventional treatment, potentially guiding future directions in clinical practice. However, further high-quality studies are needed to confirm the anti-inflammation response in the future.

Hedysarum polybotrys polysaccharide attenuates renal inflammatory infiltration and fibrosis in diabetic mice by inhibiting the HMGB1/RAGE/TLR4 pathway.

Diabetic kidney disease (DKD) is a leading cause of kidney failure. Previous studies demonstrated the therapeutic potential of Astragalus polysaccharide in treating diabetic nephropathy. Astragalus and Hongqi both come from the leguminous plant Astragalus, but their species and genera are different, belonging to the same family and different genera of traditional Chinese medicinal plants. However, the effects of Hedysarum polybotrys polysaccharide (HPS), a polysaccharide compound from Hongqi, on DKD, including its components and efficacy, have remained elusive. The present study utilized db/db mice as a DKD animal model administered with low (30 mg/kg) and high doses (60 mg/kg) of HPS, in addition to glyburide (7.2 mg/kg). Blood and urine samples were collected from mice and blood glucose, serum creatinine, urinary albumin excretion and urinary β2-microglobulin were measured. In addition, apoptosis and histological changes in kidney tissue were observed using TUNEL and HE staining, respectively, and the secretion and expression of inflammatory factors in kidney tissue were detected using EILSA and reverse transcription-quantitative PCR. Furthermore, we the expression of fibrosis-related proteins and NF-κB signaling pathway proteins was determined using western blot analysis. HPS was found to reduce the blood glucose concentration, serum creatinine levels, urinary albumin excretion rates and urinary β2-microglobulin in a dose-dependent manner. In addition, HPS treatment mitigated apoptosis and pathological damage in the kidney tissues of DKD mice. The expression levels of fibrosis-related proteins fibronectin, α-smooth muscle actin and TGF-β1 were observed to be decreased in kidney tissues of DKD mice following HPS treatment. The secretion levels of inflammatory factors (IL-6, TNF-α and IL-1β) were also reduced in kidney tissues, with high-dose HPS treatment found to be more effective, similar to the effects mediated by the glyburide. Further mechanistic analysis revealed that the therapeutic effects of HPS on DKD mice may be mediated by inhibiting the high mobility group box 1/receptor for advanced glycation end-products/toll-like receptor 4 pathway. In conclusion, the present findings could provide insight for the treatment of DKD.

Research progress on extracellular vesicles in the renal tubular injury of diabetic kidney disease.

Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes and is a chronic progressive condition. It is also a common cause of end-stage renal disease (ESRD), which is characterized by proteinuria or a progressive decline in the glomerular filtration rate. Due to their dependence on high-energy and aerobic metabolism, renal tubules are more susceptible to the metabolic disturbances associated with DKD, leading to inflammation and fibrosis. Consequently, tubular injury has become a recent research focus, and significant advancements have been made in studying the role of extracellular vesicles in DKD-associated tubular injury. This review aimed to elucidate the mechanisms and potential applications of different types of extracellular vesicles in tubular injury in DKD to provide new insights for the prevention and treatment of DKD.

Hyperoside mediates protection from diabetes kidney disease by regulating ROS-ERK signaling pathway and pyroptosis.

Renal tubular injury is a key factor in the progression of diabetic kidney disease to end-stage renal disease. Hyperoside, a natural flavonol glycoside in various plants, is a potentially effective drug for the clinical treatment of diabetic kidney disease. However, the specific mechanisms remain unknown. Therefore, this study will explore the effect and mechanism of hyperoside on renal tubulointerstitium in diabetic kidney disease. db/db mouse (C57BL/KsJ) is a model of type 2 diabetes resulting from Leptin receptor point mutations, with the appearance of diabetic kidney disease. Therefore, db/db mice were used for in vivo experimental studies. In vitro, human renal tubular epithelial cells were incubated with bovine serum albumin to simulate the injury of renal tubular epithelial cells caused by excessive albumin in primary urine. The experimental results showed that hyperoside could improve kidney function and reduce kidney tissue damage in mice, and could inhibit oxidative stress, extracellularly regulated protein kinases 1/2 signaling activation, and pyroptosis in human renal tubular epithelial cells. Therefore, hyperoside inhibited oxidative stress by regulating the activation of the extracellularly regulated protein kinases 1/2/mitogen-activated protein kinase signaling pathway, thereby alleviating proteinuria-induced pyroptosis in renal tubular epithelial cells. This study provides novel evidence that could facilitate the clinical application of hyperoside in diabetic kidney disease treatment.

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.

Mechanisms and efficacy of traditional Chinese herb monomers in diabetic kidney disease.

Diabetic kidney disease (DKD) is a serious complication of diabetes and is the primary cause of end-stage renal disease. Current treatment strategies primarily focus on the inhibition of the renin-angiotensin-aldosterone system and the attainment of blood glucose control. Although current medical therapies for DKD have been shown to delay disease progression and improve long-term outcomes, their efficacy is limited and they may be restricted in certain cases, particularly when hyperkalemia is present. Traditional Chinese medicine (TCM) treatment has emerged as a significant complementary approach for DKD. TCM monomers, derived from various Chinese herbs, have been found to modulate multiple therapeutic targets and exhibit a broad range of therapeutic effects in patients with DKD. This review aims to summarize the mechanisms of action of TCM monomers in the treatment of DKD, based on findings from clinical trials, as well as cell and animal studies. The results of these investigations demonstrate the potential effective use of TCM monomers in treating or preventing DKD, offering a promising new direction for future research in the field. By providing a comprehensive overview of the mechanisms and efficacy of TCM monomers in DKD, this review highlights the potential of these natural compounds as alternative therapeutic options for improving outcomes in patients with DKD.

Oral Chinese patent medicines for diabetic kidney disease: An overview of systematic reviews

Diabetic kidney disease (DKD) has become a global public health problem with a significant disease burden. A number of Chinese patent medicines (CPMs) are widely used in the treatment of DKD in China. An overview of systematic reviews (SRs) can summarize the overall evidence of its effectiveness and safety for both practice and research. SRs and/or meta-analyses based on randomized controlled trials (RCTs) of oral CPMs for DKD were identified. Eight databases were searched from their inception to October 2021. The AMSTAR 2 tool was applied to appraise the methodological quality of the included SRs by two authors. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to summarize the certainty of evidence of the included reviews. A total of 88 SRs were included, of which three were published as abstracts only. The methodological quality using the AMSTAR 2 approach was assessed as "low" for five SRs and "critically low" for 80 SRs. Renal end-point events and quality of life were not reported in all SRs. Most of the reviews reported surrogate outcomes. Serum creatinine and 24-hour urinary total protein were the two most commonly reported indicators, and regrettably, no high-quality evidence with GRADE assessment was found. Regarding safety, except for Tripterygium glycosides tablet, other CPMs had mild adverse effects. Due to the lack of end-point outcomes and high-quality evidence, the effectiveness and safety of oral CPMs for DKD remain uncertain. Future studies with more critical methodological designs are needed to provide robust evidence. A core outcome set for adults with DKD could help improve the consistency and relevance of outcomes from clinical trials.

SGLT2 Inhibitors in the Treatment of Diabetic Kidney Disease: More than Just Glucose Regulation.

Diabetic kidney disease (DKD) is a severe and common complication and affects a quarter of patients with type 2 diabetes mellitus (T2DM). Oxidative stress and inflammation related to hyperglycemia are interlinked and contribute to the occurrence of DKD. It was shown that sodium-glucose cotransporter-2 (SGLT2) inhibitors, a novel yet already widely used therapy, may prevent the development of DKD and alter its natural progression. SGLT2 inhibitors induce systemic and glomerular hemodynamic changes, provide metabolic advantages, and reduce inflammatory and oxidative stress pathways. In T2DM patients, regardless of cardiovascular diseases, SGLT2 inhibitors may reduce albuminuria, progression of DKD, and doubling of serum creatinine levels, thus lowering the need for kidney replacement therapy by over 40%. The molecular mechanisms behind these beneficial effects of SGLT2 inhibitors extend beyond their glucose-lowering effects. The emerging studies are trying to explain these mechanisms at the genetic, epigenetic, transcriptomic, and proteomic levels.

Loganin reduces diabetic kidney injury by inhibiting the activation of NLRP3 inflammasome-mediated pyroptosis

Diabetic kidney disease (DKD) is an essential cause of end-stage renal disease. The ongoing inflammatory response in the proximal tubule promotes the progression of DKD. Timely and effective blockade of the inflammatory process to protect the kidney during DKD progression is a proven strategy. The purpose of this study was to investigate the protective effect of loganin on diabetic nephropathy in vivo and in vitro and whether this effect was related to the inhibition of pyroptosis. The results indicated that loganin reduced fasting blood glucose, blood urea nitrogen and serum creatinine concentrations, and alleviated renal pathological changes in DKD mice. In parallel, loganin downregulated the expression of pyroptosis related proteins in the renal tubules of DKD mice and decreased serum levels of interleukin-1beta (IL-1β) and interleukin-18 (IL-18). Furthermore, in vitro experiments showed that loganin attenuated high glucose-induced HK-2 cell injury by reducing the expression of pyroptosis-related proteins, and cytokine levels were also decreased. These fundings were also confirmed in the polyphyllin VI (PPVI) -induced HK-2 cell pyroptosis model. Loganin reduces high glucose induced HK-2 cells pyroptosis by inhibiting reactive oxygen species (ROS) production and NOD-like receptor protein 3 (NLRP3) inflammasome activation. In conclusion, the inhibition of pyroptosis via inhibition of the NLRP3/Caspase-1/Gasdermin D (GSDMD) pathway might be an essential mechanism for loganin treatment of DKD.

Huangkui capsule attenuates diabetic kidney disease through the induction of mitophagy mediated by STING1/PINK1 signaling in tubular cells

BackgroundMitochondria is critic to tubulopathy, especially in diabetic kidney disease (DKD). Huangkui capsule (HKC; a new ethanol extract from the dried corolla of Abelmoschus manihot) has significant clinical effect on DKD. Previous studies have shown that HKC protects kidney by regulating mitochondrial function, but its mechanism is still unclear. The latest research found that the stimulator of interferon genes (STING1) signal pathway is closely related to mitophagy. However, whether HKC induces mitophagy through targeting STING1/PTEN-Induced putative kinase (PINK1) in renal tubular remains elusive. ObjectiveThis study aims to clarify the therapeutic effect of HKC on renal tubular mitophagy in DKD and its potential mechanism in vivo and in vitro. MethodsForty male C57BL/6 mice were randomly divided into 5 groups: CON group, DKD group, HKC-L (1.0 g/kg/day, by gavage), HKC-H (2.0 g/kg/day), and LST group. Diabetes model was induced by high-fat diet (HFD) combined with intraperitoneal injection of Streptozotocin (STZ). LST (losartan) is used as a positive control drug. Then, the glomeruli, renal tubular lesions, mitochondrial morphology and function of renal tubular cells and mitophagy levels were detected in mice. In addition, a high glucose injury model was established using HK2 human renal tubular cells. Pretreate HK2 cells with HKC or LST and detect mitochondrial function, mitophagy level, and autophagic flux. In addition, small interfering RNAs (siRNAs) of STING1 and PINK1 and overexpressing pcDNA3.1 plasmids were transfected into HK-2 cells to validate the mitophagy mechanism regulated by STING1/PINK1 signaling. ResultsThe ratio of urinary albumin to creatinine (ACR), fasting blood glucose, body weight in the early DKD mice model was increased, with damage to the glomerulus and renal tubules, mitochondrial structure and dysfunction in the renal tubules, and inhibition of STING1/PINK1 mediated mitophagy. Although the fasting blood glucose, body weight and serum creatinine levels were hardly ameliated, high dose HKC (2.0 g/kg/day) treatment significantly reduced ACR in the DKD mice to some extent, improved renal tubular injury, accurately upregulated STING1/PINK1 signaling mediated mitophagy levels, improved autophagic flux, and restored healthy mitochondrial pools. In vitro, an increase in mitochondrial fragments, fusion to fission, ROS and apoptosis, and a decrease in respiratory function, mtDNA, and membrane potential were observed in HK2 cells exposed to high glucose. HKC treatment significantly protected mitochondrial dynamics and function, which is consistent with in vivo results. Further research has shown that HKC can increase the level of mitophagy mediated by STING1/PINK1 in HK2 cells. ConclusionsOur results suggest that HKC ameliorates renal tubulopathy in DKD and induces mitophagy partly through the up-regulation of the STING1/PINK1 pathway. These findings may provide an innovative therapeutic basis for DKD treatment.

A Systematic Review and Meta-Analysis on the Efficacy and Safety of Finerenone Therapy in Patients with Cardiovascular and Chronic Kidney Diseases in Type 2 Diabetes Mellitus.

The purpose of this study is to assess the safety and efficacy of finerenone therapy in type 2 diabetes mellitus (T2DM) patients with cardiovascular and chronic renal diseases. This meta-analysis assesses the efficacy and safety of finerenone in the treatment of diabetic kidney disease (DKD).A comprehensive search of PubMed, Embase, and Google Scholar databases was performed to identify relevant randomized controlled trials (RCTs). To quantify the effects of finerenone, the analysis included the estimation of aggregated mean differences (MDs) and relative risks (RRs), as well as 95% confidence intervals (CIs). This meta-analysis included seven double-blind trials with patients suffering from chronic kidney disease (CKD) and T2D. Participants received finerenone or a placebo was assigned at random. The primary efficacy outcomes were cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, hospitalization for heart failure, kidney failure, a sustained 57% decrease in the estimated glomerular filtration rate from baseline over four weeks, or renal death. Among the 39,995 patients included in the analysis, finerenone treatment was associated with a lower risk of cardiovascular and renal-related mortality compared to placebo (RR = 0.86 (0.80, 0.93), p = 0.0002; I-squared statistic(I2)= 0%) and (RR = 0.56 (0.17, 1.82), p = 0.34; I2= 0%). In addition, finerenone treatment was associated with a marginally reduced risk of serious adverse events (RR = 0.95 (0.92, 0.97), p = 0.0001; I2= 0%), although no significant difference in the overall risk of adverse events was observed between the two groups (RR = 1.00 (0.99, 1.01), p = 0.56; I2= 0%). This study's findings suggest that finerenone administration can reduce the risk of end-stage kidney disease, renal failure, cardiovascular mortality, and hospitalization. Patients with both T2DM and CKD are therefore advised to consider finerenone therapy.

Exploring Heterogeneity with Category and Cluster Analyses for Mixed Data

Precision medicine aims to overcome the traditional one-model-fits-the-whole-population approach that is unable to detect heterogeneous disease patterns and make accurate personalized predictions. Heterogeneity is particularly relevant for patients with complications of type 2 diabetes, including diabetic kidney disease (DKD). We focus on a DKD longitudinal dataset, aiming to find specific subgroups of patients with characteristics that have a close response to the therapeutic treatment. We develop an approach based on some particular concepts of category theory and cluster analysis to explore individualized modelings and achieving insights onto disease evolution. This paper exploits the visualization tools provided by category theory, and bridges category-based abstract works and real datasets. We build subgroups deriving clusters of patients at different time points, considering a set of variables characterizing the state of patients. We analyze how specific variables affect the disease progress, and which drug combinations are more effective for each cluster of patients. The retrieved information can foster individualized strategies for DKD treatment.

Clinical Efficacy of Dapagliflozin in the Treatment of Patients with Diabetic Nephropathy and Its Effect on Proteinuria Level.

This study aimed to analyze the clinical efficacy of dapagliflozin in the treatment of diabetic kidney disease and its impact on proteinuria levels in patients. Retrospective analysis of medical records of 176 patients with diabetic kidney disease treated at our hospital from January 2020 to January 2022. According to the different treatment methods, the patients were divided into a control group (n=88) receiving enalapril maleate treatment and an observation group (n=88) receiving dapagliflozin treatment. The clinical treatment effects, blood glucose levels, renal function indicators, inflammation factor indicators, and adverse reactions were compared between the two groups. The total effective rate of treatment (97.73%) in the observation group was significantly higher than that (79.55%) in the control group (P<0.05). After treatment, the FPG, 2hPG, and HbAlc levels in the observation group were significantly lower than those in the control group (P<0.05). After treatment, the Scr, BUN, UmAlb, UAER, UACR, and 24-hour urine protein quantitative levels in the observation group were significantly lower than those in the control group (P<0.05). After treatment, the hs-CRP, IL-1β, and TNF-α levels in the observation group were significantly lower than those in the control group (P<0.05). The incidence of adverse reactions in the observation group significantly lower than the control group (P<0.05). Compared with enalapril maleate alone, the combined application of dapagliflozin in the treatment of diabetic kidney disease has more significant clinical efficacy. It can further control patients' blood sugar, reduce their body's inflammatory response, alleviate or eliminate their proteinuria symptoms, promote the recovery of their renal function, and enhance the safety of their treatment to a certain extent, which helps to further improve the clinical treatment effect of patients.

The role of microbial metabolites in diabetic kidney disease

BackgroundGrowing evidence suggests a complex bidirectional interaction between gut microbes, gut-derived microbial metabolites, and diabetic kidney disease (DKD), known as the “gut-kidney axis” theory. The present study aimed to characterize the role of microbial metabolites in DKD. MethodsSix-week-old db/db and littermate db/m mice were raised to 20 weeks old. The serum, urine, feces, liver, perinephric fat, and kidney were analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based metabolomic analyses. ResultsThe db/db mice showed obvious pathological changes and worse renal functions than db/m mice. Indoleacetaldehyde (IAld) and 5-hydroxy-l-tryptophan (5-HTP) in kidney samples, and serotonin (5-HT) in fecal samples were increased in the db/db group. Phosphatidylcholine (PC), phosphatidate (PA), and 1-acylglycerophosphocholine (lysoPC) were decreased in liver and serum samples of the db/db group, while PC and lysoPC were decreased in kidney and perinephric fat samples. Suggested metabolomic homeostasis was disrupted in DKD mice, especially glycerophospholipid and tryptophan metabolism, which are closely related to the gut microbiome. ConclusionsOur findings reveal the perturbation of gut microbial metabolism in db/db mice with DKD, which may be useful for building a bridge between the gut microbiota and the progression of DKD and provide a theoretical basis for the intestinal treatment of DKD.

Therapy for CKD and DKD

Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Specific remedies are needed for preventing Type 2 diabetes which causes significant changes in an array of plasma metabolites. By untargeted metabolome analysis, phenyl sulfate (PS) increased with the progression of diabetes. In experimental diabetes models, PS administration induces albuminuria and podocyte damage due to the mitochondrial dysfunction. By clinical diabetic kidney disease (DKD) cohort analysis, it was also confirmed that the PS levels significantly correlate with basal and predicted 2-year progression of albuminuria. Phenol is synthesized from dietary tyrosine by gut bacterial-specific tyrosine phenol-lyase (TPL), and absorbed phenol is metabolized into PS in the liver. Inhibition of TPL reduces not only the circulating PS level but also albuminuria in diabetic mice. TPL inhibitor did not significantly alter the major composition, showing the non-lethal inhibition of microbial-specific enzymes has a therapeutic advantage, with lower selective pressure for the development of drug resistance. Clinically, 362 patients in a multi-center clinical study in diabetic nephropathy cohort (U-CARE) were analyzed with full data. The basal plasma PS level significantly correlated with ACR, eGFR, age, duration, HbA1c and uric acid, but not with suPAR. Multiple regression analysis revealed that ACR was the only factor that significantly correlated with PS. By stratified logistic regression analysis, in the microalbuminuria group, PS was the only factor related to the amount of change in the 2-year ACR in all models. PS is not only an early diagnosis marker, but also a modifiable cause and therefore a target for the treatment of DKD. Reduction of microbiota-derived phenol by the inhibitor should represent another aspect for developing drugs of DKD prevention.

Based on Literature Research to Explore the Theoretical Connotation of Tonifying Qi, Nourishing Yin, Activating Blood and Dredging Collaterals in the Treatment of Diabetic Kidney Disease

Based on Literature Research to Explore the Theoretical Connotation of Tonifying Qi, Nourishing Yin, Activating Blood and Dredging Collaterals in the Treatment of Diabetic Kidney Disease

Epigenetic modification in diabetic kidney disease.

Diabetic kidney disease (DKD) is a common microangiopathy in diabetic patients and the main cause of death in diabetic patients. The main manifestations of DKD are proteinuria and decreased renal filtration capacity. The glomerular filtration rate and urinary albumin level are two of the most important hallmarks of the progression of DKD. The classical treatment of DKD is controlling blood glucose and blood pressure. However, the commonly used clinical therapeutic strategies and the existing biomarkers only partially slow the progression of DKD and roughly predict disease progression. Therefore, novel therapeutic methods, targets and biomarkers are urgently needed to meet clinical requirements. In recent years, increasing attention has been given to the role of epigenetic modification in the pathogenesis of DKD. Epigenetic variation mainly includes DNA methylation, histone modification and changes in the noncoding RNA expression profile, which are deeply involved in DKD-related inflammation, oxidative stress, hemodynamics, and the activation of abnormal signaling pathways. Since DKD is reversible at certain disease stages, it is valuable to identify abnormal epigenetic modifications as early diagnosis and treatment targets to prevent the progression of end-stage renal disease (ESRD). Because the current understanding of the epigenetic mechanism of DKD is not comprehensive, the purpose of this review is to summarize the role of epigenetic modification in the occurrence and development of DKD and evaluate the value of epigenetic therapies in DKD.