Causal relationship between gut microbiota and chronic renal failure: a two-sample Mendelian randomization study.

Background: Observational studies and some experimental investigations have indicated that gut microbiota are closely associated with the incidence and progression of chronic renal failure. However, the causal relationship between gut microbiota and chronic renal failure remains unclear. The present study employs a two-sample Mendelian randomization approach to infer the causal relationship between gut microbiota and chronic renal failure at the genetic level. This research aims to determine whether there is a causal effect of gut microbiota on the risk of chronic renal failure, aiming to provide new evidence to support targeted gut therapy for the treatment of chronic renal failure. Methods: Employing genome-wide association study (GWAS) data from the public MiBioGen and IEU OpenGWAS platform, a two-sample Mendelian randomization analysis was conducted. The causal relationship between gut microbiota and chronic renal failure was inferred using five different methods: Inverse Variance Weighted, MR-Egger, Weighted Median, Simple Mode, and Weighted Mode. The study incorporated sensitivity analyses that encompassed evaluations for pleiotropy and heterogeneity. Subsequently, the results of the Mendelian randomization analysis underwent a stringent correction for multiple testing, employing the False Discovery Rate method to enhance the validity of our findings. Results: According to the results from the Inverse Variance Weighted method, seven bacterial genera show a significant association with the outcome variable chronic renal failure. Of these, Ruminococcus (gauvreauii group) (OR = 0.82, 95% CI = 0.71-0.94, p = 0.004) may act as a protective factor against chronic renal failure, while the genera Escherichia-Shigella (OR = 1.22, 95% CI = 1.08-1.38, p = 0.001), Lactococcus (OR = 1.1, 95% CI = 1.02-1.19, p = 0.013), Odoribacter (OR = 1.23, 95% CI = 1.03-1.49, p = 0.026), Enterorhabdus (OR = 1.14, 95% CI = 1.00-1.29, p = 0.047), Eubacterium (eligens group) (OR = 1.18, 95% CI = 1.02-1.37, p = 0.024), and Howardella (OR = 1.18, 95% CI = 1.09-1.28, p < 0.001) may be risk factors for chronic renal failure. However, after correction for multiple comparisons using False Discovery Rate, only the associations with Escherichia-Shigella and Howardella remain significant, indicating that the other genera have suggestive associations. Sensitivity analyses did not reveal any pleiotropy or heterogeneity. Conclusion: Our two-sample Mendelian randomization study suggests that the genera Escherichia-Shigella and Howardella are risk factors for chronic renal failure, and they may serve as potential targets for future therapeutic interventions. However, the exact mechanisms of action are not yet clear, necessitating further research to elucidate their precise roles fully.

Circulating galectin-3 level association with cardiovascular risk factors during peritoneal dialysis.

OBJECTIVE: Cardiovascular disease (CVD) represents the primary cause of mortality in patients afflicted with end-stage renal disease and undergoing peritoneal dialysis (PD) treatment. Galectin-3 (Gal-3), a molecule known to exhibit a correlation with CVD mortality garners considerable interest. The objective of this study was to explore the potential association between serum Gal-3 levels and other CVD risk factors among PD patients. METHODS: In this cross-sectional study, a total of 114 PD patients with a minimum of 3 months of PD treatment were enrolled. Serum Gal-3 levels were quantified using an enzyme-linked immunosorbent assay. The data of patients with Gal-3 levels higher and lower than 26.744 pg/ml were compared using Mann-Whitney U tests or t tests. Pearson's correlation or Spearman's correlation analysis and multivariate regression were used to assess the associations between the known risk factors for CVD and Gal-3. RESULTS: In comparison to the inter-group baseline data, the low Gal-3 group exhibited a higher glomerular filtration rate (GFR). Gal-3 levels correlate positively with PD duration, B-type natriuretic peptide (BNP), growth differentiation factor 15 (GDF-15), interventricular septal thickness in diastolic (IVST), and left ventricular mass index (LVMI). Conversely, Gal-3 exhibited a negative correlation with albumin levels. Multivariate linear regression analysis demonstrated a positive correlation between Gal-3 levels and BNP, GDF-15, PD duration, IVST and LVMI. Gal-3 levels were negatively correlated with albumin levels. CONCLUSIONS: Gal-3 was strongly associated with BNP, GDF-15, IVST and LVMI in patients undergoing PD treatment. Prospective studies should be carried out to determine whether Gal-3 can be a promising biomarker in predicting increased risk of adverse cardiovascular events in PD patients.

Insights into serum metabolic biomarkers for early detection of incident diabetic kidney disease in Chinese patients with type 2 diabetes by random forest.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD) worldwide. Early detection is critical for the risk stratification and early intervention of progressive DKD. Serum creatinine (sCr) and urine output are used to assess kidney function, but these markers are limited by their delayed changes following kidney pathology, and lacking of both sensitivity and accuracy. Hence, it is essential to illustrate potential diagnostic indicators to enhance the precise prediction of early DKD. A total of 194 Chinese individuals include 30 healthy participants (Stage 0) and 164 incidents with type 2 diabetes (T2D) spanning from DKD's Stage 1a to 4 were recruited and their serums were subjected for untargeted metabolomic analysis. Random forest (RF), a machine learning approach, together with univariate linear regression (ULR) and multivariate linear regression (MvLR) analysis were applied to characterize the features of untargeted metabolites of DKD patients and to identify candidate DKD biomarkers. Our results indicate that 2-(α-D-mannopyranosyl)-L-tryptophan (ADT), succinyladenosine (SAdo), pseudouridine and N,N,N-trimethyl-L-alanyl-L-proline betaine (L-L-TMAP) were associated with the development of DKD, in particular, the latter three that were significantly elevated in Stage 2-4 T2D incidents. Each of the four metabolites in combination with sCr achieves better performance than sCr alone with area under the receiver operating characteristic curve (AUC) of 0.81-0.91 in predicting DKD stages. An average of 3.9 years follow-up study of another cohort including 106 Stage 2-3 patients suggested that "urinary albumin-to-creatinine ratio (UACR) + ADT + SAdo" can be utilized for better prognosis evaluation of early DKD (average AUC = 0.9502) than UACR without sexual difference.

Artemether ameliorates type 2 diabetic kidney disease by increasing mitochondrial pyruvate carrier content in db/db mice.

Diabetic kidney disease (DKD), the leading cause of kidney failure, is characterized by albuminuria and renal hypertrophy. Metabolic alterations and mitochondrial dysfunction play critical roles in DKD initiation and progression. Artemether, a methyl ether derivative of artemisinin used for the treatment of malaria, has been identified as a putative candidate for treating diabetes, but its effect on DKD has not been studied. The goal of this study was to examine the effect of artemether on type 2 diabetic db/db mice. Our results show that artemether reduced urinary albumin excretion, prevented diabetic kidney hypertrophy, attenuated glomerular basement membrane and tubular basement membrane thickening, and ameliorated foot process effacement in type 2 diabetic db/db mice. Artemether also protected against hyperglycemia and improved diabetic symptoms. In addition, it increased serum insulin level and restored the normal ratio of insulin, glucagon, and somatostatin levels in islets. Specifically, artemether increased the respiratory exchange ratio and regulated mitochondrial function and the redox state in the kidney. In conclusion, this experiment confirmed the renal protection ability of artemether in DKD. The mechanisms of this effect might be associated with the ability of artemether to increase mitochondrial pyruvate carrier content.

Niclosamide ethanolamine improves kidney injury in db/db mice.

AIMS: Early diabetic kidney disease (DKD) is characterized by renal hypertrophy and albuminuria. The mTOR signal pathway is closely related to DKD. This study was performed to determine the renal protection of niclosamide ethanolamine salt (NEN) which was identified as mTOR inhibitor. METHODS: Type 2 diabetes (T2D) db/db mice were used and divided into db/db and db/db + NEN groups. Lean wild type mice served as T2D-control. NEN treatment lasted for 12 weeks. The kidney morphological changes, urine indices, blood glucose and metabolic symptoms were evaluated. In addition, the effects of NEN on kidney mitochondria and mTOR/4E-BP pathway were also measured. RESULTS: NEN could prevent diabetic kidney hypertrophy and alleviate glomerular mesangial expansion, attenuate GBM and TBM thickening in db/db mice. It also restored podocyte dysfunction, reduced urinary albumin, NAG, NGAL, and TGF-ß1 excretion. Specifically, it could uncouple kidney mitochondria and significantly inhibit renal cortical activation of mTOR/4E-BP1 pathway. CONCLUSIONS: This study demonstrated that NEN could improve kidney injury in db/db mice and has the potential to translate to future clinical studies.

Astragaloside IV ameliorates early diabetic nephropathy by inhibition of MEK1/2-ERK1/2-RSK2 signaling in streptozotocin-induced diabetic mice.

Objective The aim of this study was to investigate the renoprotective effects and molecular mechanisms of astragaloside IV (AS-IV) in streptozotocin (STZ)-induced diabetic mice. Methods Male C57BL/6 mice were injected intraperitoneally with STZ at 200 mg/kg body weight. AS-IV was administered for 8 consecutive weeks, beginning 1 week after STZ injection. Body weight, 24-hour urinary albumin excretion, and fasting blood glucose were measured. Kidney tissues were examined by histopathological analyses. Total levels and phosphorylation of mitogen-activated protein kinase 1/2 (MEK1/2), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and ribosomal S6 kinase 2 (RSK2) were determined by Western blotting analysis. Results AS-IV treatment significantly reduced albuminuria and serum creatinine levels, ameliorated mesangial matrix expansion and greater foot process width, and decreased the levels of urinary N-acetyl-beta-D-glucosaminidase, neutrophil gelatinase-associated lipocalin, and transforming growth factor-beta 1 in STZ-induced diabetic mice. AS-IV also inhibited renal cortical phosphorylation of MEK1/2, ERK1/2 and RSK2. Conclusion Our results suggest that AS-IV attenuates renal injury in STZ-induced diabetic mice. This effect might be partially associated with inhibition of the activation of the MEK1/2-ERK1/2-RSK2 signaling pathway.

Niclosamide ethanolamine improves diabetes and diabetic kidney disease in mice.

Diabetes and its renal complications are major medical challenges worldwide. There are no effective drugs currently available for treating diabetes and diabetic kidney disease (DKD), especially in type 1 diabetes (T1D). Evidence has suggested that niclosamide ethanolamine salt (NEN) could improve diabetic symptoms in mice of type 2 diabetes (T2D). However, its role in T1D and DKD has not been studied to date. Here we report that NEN could protect against diabetes in streptozotocin (STZ) induced T1D mice. It increased serum insulin levels, corrected the unbalanced ratio of α-cells to ß-cells, and induced islet morphologic changes under diabetic conditions. In addition, NEN could impede the progression of DKD in T1D. Specifically, it reduced urinary albumin levels, NAG, NGAL and TGF-ß1 excretion, ameliorated renal hypertrophy, alleviated podocyte dysfunction, and suppressed the renal cortical activation of mTOR/4E-BP1 signaling pathway. Moreover, it is hepatoprotective and does not exhibit heart toxicity. Therefore, these findings open up a completely novel therapy for diabetes and DKD.

Resveratrol Improves Muscle Atrophy by Modulating Mitochondrial Quality Control in STZ-Induced Diabetic Mice.

SCOPE: In this study, we aim to determine the effects of resveratrol (RSV) on muscle atrophy in streptozocin-induced diabetic mice and to explore mitochondrial quality control (MQC) as a possible mechanism. METHODS AND RESULTS: The experimental mice were fed either a control diet or an identical diet containing 0.04% RSV for 8 weeks. Examinations were subsequently carried out, including the effects of RSV on muscle atrophy and muscle function, as well as on the signaling pathways related to protein degradation and MQC processes. The results show that RSV supplementation improves muscle atrophy and muscle function, attenuates the increase in ubiquitin and muscle RING-finger protein-1 (MuRF-1), and simultaneously attenuates LC3-II and cleaved caspase-3 in the skeletal muscle of diabetic mice. Moreover, RSV treatment of diabetic mice results in an increase in mitochondrial biogenesis and inhibition of the activation of mitophagy in skeletal muscle. RSV also protects skeletal muscle against excess mitochondrial fusion and fission in the diabetic mice. CONCLUSION: The results suggest that RSV ameliorates diabetes-induced skeletal muscle atrophy by modulating MQC.

A Chinese herbal formula, Jian-Pi-Yi-Shen decoction, improves muscle atrophy via regulating mitochondrial quality control process in 5/6 nephrectomised rats.

Muscle atrophy is one of the serious complications of chronic kidney disease (CKD). Dysregulation of mitochondrial quality control (MQC) process, including decrease mitochondrial biogenesis, impair mitochondrial dynamics and induce activation of mitophagy, play an important role in mediating muscle wasting. This study aimed to observe effects of Jian-Pi-Yi-Shen (JPYS) decoction on muscle atrophy in CKD rats and explore its possible mechanism on regulation of MQC processes. The 5/6 nephrectomised rats were randomly allocated into 2 groups: CKD group and JPYS group. Besides, a sham-operated rats as sham group. All rats were treated for 6 weeks. Results showed that administration of JPYS decoction prevented body weight loss, muscle loss, muscle fiber size decrease, muscle protein degradation, and increased muscle protein systhesis. In addition, JPYS decoction increased the mitochondrial content and biogenesis proteins, and down-regulated the autophagy and mitophagy proteins. Furthermore, JPYS decoction increased mitochondrial fusion proteins, while decreased mitochondrial fission proteins. In conclusion, JPYS decoction increased mitochondrial content and biogenesis, restore the balance between fission and fusion, and inhibited autophagy-lysosome pathway (mitophagy). Collectively, our data showed that JPYS decoction to be beneficial to muscle atrophy in CKD, which might be associated with the modulation of MQC process.

Astragaloside IV ameliorates diabetic nephropathy by modulating the mitochondrial quality control network.

The aim of this study was to investigate the effect and possible mechanism of Astragaloside IV (AS-IV) on retarding the progression of diabetic nephropathy (DN) in a type 2 diabetic animal model, db/db mice. Eight-week-old male db/db diabetic mice and their nondiabetic littermate control db/m mice were used in the present study. AS-IV was administered to the db/db mice by adding it to standard feed at a dose of 1g/kg for 12 weeks. Renal injury was assessed by urinary albumin excretion (UAE) and Periodic acid-Schiff staining. The protein expression levels of mitochondrial quality-control-associated proteins were evaluated using Western blotting and immunohistochemical staining analysis. At the end of the experiment, db/db mice showed overt renal injury, as evidenced by increased UAE, increased urinary N-acetyl-ß-D-glucosaminidase (NAG), expansion of mesangial matrix, and increased renal tubular area. AS-IV administration significantly reduced UAE and urinary NAG and ameliorated the renal pathologic injury seen in db/db mice. Furthermore, the expression of dynamin-related protein 1 (Drp-1), mitochondrial fission protein 1 (Fis-1), and mitochondrial fission factor (MFF), the main regulators of mitochondrial fission, was significantly increased in db/db mice. Moreover, PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy was abnormally activated in db/db mice. AS-IV significantly reduced renal Drp-1, Fis-1, and MFF expression and downregulated PINK1/Parkin-mediated mitophagy in db/db mice. However, mitochondrial biogenesis and mitochondrial fusion-associated protein levels were not significantly different between db/m and db/db mice in our study, with or without AS-IV treatment. In conclusion, administration of AS-IV could retard DN progression in type 2 diabetes mice, which might be associated with restoration of the mitochondrial quality control network.

Astragaloside IV ameliorates renal injury in db/db mice.

Diabetic nephropathy is a lethal complication of diabetes mellitus and a major type of chronic kidney disease. Dysregulation of the Akt pathway and its downstream cascades, including mTOR, NFκB, and Erk1/2, play a critical role in the development of diabetic nephropathy. Astragaloside IV is a major component of Huangqi and exerts renal protection in a mouse model of type 1 diabetes. The current study was undertaken to investigate the protective effects of diet supplementation of AS-IV on renal injury in db/db mice, a type 2 diabetic mouse model. Results showed that administration of AS-IV reduced albuminuria, ameliorated changes in the glomerular and tubular pathology, and decreased urinary NAG, NGAL, and TGF-ß1 in db/db mice. AS-IV also attenuated the diabetes-related activation of Akt/mTOR, NFκB, and Erk1/2 signaling pathways without causing any detectable hepatotoxicity. Collectively, these findings showed AS-IV to be beneficial to type 2 diabetic nephropathy, which might be associated with the inhibition of Akt/mTOR, NFκB and Erk1/2 signaling pathways.