Zhen-Wu-Tang Induced Mitophagy to Protect Mitochondrial Function in Chronic Glomerulonephritis via PI3K/AKT/mTOR and AMPK Pathways

Chronic glomerulonephritis (CGN) is one of the major causes of end-stage kidney disease. Zhen-wu-tang (ZWT), as a famous Chinese herbal prescription, is widely used in China for CGN therapy in clinic. However, the mechanism of ZWT in CGN has not been fully understood. The present study explored the therapeutic effect and the underlying mechanism of ZWT on mitochondrial function in cationic bovine serum albumin (C-BSA)-induced CGN model rats and tumor necrosis factor (TNF-α)-damaged mouse podocytes. The renal functions were measured by serum creatinine (Scr) and blood urea nitrogen (BUN). Renal pathological changes and ultrastructure of kidney tissues were evaluated by periodic acid-Schiff (PAS) staining and transmission electron microscopy. The levels of antioxidases, including mitochondrial catalase (CAT), superoxide dismutase 2 (SOD2), and peroxiredoxin 3 (PRDX3), in CGN rats were examined by real-time PCR. The mitochondrial functions of podocytes were measured by ATP concentration, mitochondrial membrane potential (MMP), and mitochondrial ROS (mtROS). For mitophagy level detection, the expressions of mitophagy-related proteins, including LC3, p62, heat shock protein 60 (HSP60), and translocase of outer mitochondrial membrane 20 (TOMM20), were measured by Western blot, as the colocation of LC3 and mitochondrial marker COX IV were evaluated by immunofluorescence. Our results manifested that ZWT ameliorated CGN model rats by a remarkable decrease in Scr and BUN, inhibition of mesangial matrix proliferation, protection against foot processes fusion, and basement membrane thickening. More importantly, ZWT protected against mitochondrial dysfunction by increasing the expressions of CAT, SOD2, and PRDX3 in CGN model rats, increased ATP content and MMP in podocytes, and decreased excessive mtROS. Furthermore, ZWT induced mitophagy in CGN through increasing the expression of LC3, and decreasing p62, HSP60, TOMM20, and ZWT also enhanced the colocation of LC3 to the mitochondria. We found that ZWT inhibited the PI3K/AKT/mTOR pathway, which could be disturbed by PI3K inhibitor LY294002 and agonist insulin-like growth factor 1. Moreover, ZWT reversed the inhibition of the AMPK pathway in CGN. Overall, ZWT ameliorated renal mitochondrial dysfunction probably by inducing mitophagy via the PI3K/AKT/mTOR and AMPK pathways.

Assessment of Proximal Radio-median Cubital/Radio-Cephalic Arterio-venous Fistula

The present study aims to conducted the Assessment of Proximal radio-median cubital/radio-cephalic Arterio-venous Fistula. Arterio-venous Fistula is life line for long-term hemodialysis for end stage renal disease patients. The order of preference as per National Kidney Foundation/ Kidney Disease Out Come Quality Initiative (KDOQI) is distal Radio Cephalic fistula is considered as gold standard followed by elbow Brachio Cephalic Fistula, transposed Brachio-Basilic Fistula, forearm arterio-venous graft. This is a cross sectional-prospective interventional study, 05/2017 to 04/2019, JNMC, Wardha, MH, with sample size of 66 cases. Out of 66 cases 25 % patients had diabetes mellitus, 48% cases were suffering from chronic glomerulonephritis, 15 % cases were suffering hypertension, 6 % cases had COPD and another 6 % cases had some cardiovascular disease. About 54 % cases had previous access failure. In our study the mean flow volume for AV fistula in proximal forearm was 485± 291 ml/minon postoperative day1, 695 ± 298 on postoperative day 7 and 755± 347 ml/min. Overall postoperative complications in 12% cases was reported in our case study though Yilmiz et al reported postoperative complications in 15% cases.

Total flavone of Abelmoschus Manihot improves colitis by promoting the growth of Akkermansia in mice

The total flavone of Abelmoschus manihot (TFA), a compound extracted from the flowers of Abelmoschus manihot (L.) Medic, has been widely used for the treatment of Crohn's disease, chronic glomerulonephritis and other diseases. The aim of this study was to investigate the effect of TFA on the gut microbiota and intestinal barrier in dextran sulfate sodium (DSS)-induced experimental colitis. C57BL/6J mice were treated with 2.5% DSS in drinking water to induce colitis. Mice were orally administered TFA (62.5 mg/kg, 125 mg/kg) or prednisone acetate (PAT, 2.5 mg/kg) once daily for 7 days. Biological samples were collected for analysis of inflammatory cytokines, gut microbiota and intestinal barrier integrity. TFA-H (125 mg/kg) markedly attenuated DSS-induced colon shortening and histological injury in experimental colitis. The therapeutic effect was similar to that of PAT administration. TFA-H notably modulated the dysbiosis of gut microbiota induced by DSS and greatly enriched Akkermansia muciniphila (A. muciniphila). Moreover, TFA-H remarkably ameliorated the colonic inflammatory response and intestinal epithelial barrier dysfunction. Interestingly, TFA directly promotes the growth of A. muciniphila in vitro. Taken together, the results revealed for the first time that TFA, as a prebiotic of A. muciniphila, improved DSS-induced experimental colitis, at least partly by modulating the gut microflora profile to maintain colonic integrity and inhibit the inflammatory response.

Native T1 Mapping in Assessing Kidney Fibrosis for Patients With Chronic Glomerulonephritis

Purpose: To assess the utility of non-contrast enhanced native T1 mapping of the renal cortex in assessing renal fibrosis for patients with chronic glomerulonephritis (CGN).Methods: A total of 119 patients with CGN and 19 healthy volunteers (HVs) were recruited for this study. Among these patients, 43 had undergone kidney biopsy measurements. Clinical information and biopsy pathological scores were collected. According to the results of the renal biopsy, the patients were classified into the high (25–50%), low (<25%) and no renal interstitial fibrosis (IF) (0%) groups. The correlations between the T1 value in the renal cortex and each of the clinical parameters were separately analyzed. The relationships between each fibrosis group and the T1 value were also evaluated and compared between groups. Binary logistic regression analysis was further used to determine the relationship between the T1 value and renal fibrosis. Receiver operating characteristic (ROC) curves were plotted to analyze the diagnostic value of the T1 value for renal fibrosis.Results: Compared with those of the HVs, the T1 values were significantly higher in patients at all stages of chronic kidney disease (CKD) (all p < 0.05). Significant T1 differences were also revealed between patients with different stages of CKD (p < 0.05). Additionally, the T1 value correlated well with CKD stage (p < 0.05), except between CKD 2 and 3. In addition, the T1 value was positively correlated with cystatin C, neutrophil gelatinase-associated lipocalin, and serum creatinine and negatively correlated with hemoglobin, kidney length, estimated glomerular filtration rate and hematocrit (all p < 0.05). Compared with those of the no IF group, the T1 values were increased in the low- and high-IF groups (both p < 0.05). Logistic regression analysis showed that an elevated T1 value was an independent risk factor for renal fibrosis. ROC analysis suggested that the optimal critical value of T1 for predicting renal fibrosis was 1,695 ms, with a specificity of 0.778 and a sensitivity of 0.625.Conclusion: Native T1 mapping demonstrated good diagnostic performance in evaluating renal function and was an effective noninvasive method for detecting renal fibrosis in CGN patients.

Measurement of Inflammation-Related Biomarkers in Different Chronic Kidney Diseases in Humans: Role of Aging and Gender?

INTRODUCTION: Chronic kidney disease (CKD) is a worldwide health problem which becomes a substantial emerging cause of morbidity. The inflammation can be resulted via different mechanisms in different kidney diseases including the imbalance of proinflammatory/anti-inflammatory biomarkers levels. This study aimed to measure the level of physiological bioactive substances as inflammation-related biomarkers in different CKD and to investigate whether gender or aging is critical in these measurements. MATERIALS AND METHODS: 84 persons (19 healthy, 29 chronic glomerulonephritis, 26 diabetic nephropathy, 6 benign nephrosclerosis, 4 lupus nephritis) were enrolled in this study. The inflammation progression degree in CKD was estimated by measuring the plasma level of neutrophil gelatinase-associated lipocalin (NGAL), monocyte chemoattractant protein 1 (MCP1), and clusterin (CLU) using ELISA. Serum total protein, urea and creatinine were measured using an automatic analyzer. RESULTS: Plasma level of urea and creatinine was increased while total protein level was decreased in all the patients compared to control participants. The level of NGAL, MCP1 and CLU was significantly increased in all the kidney diseases compared to controls. In addition, there were no differences in the level of inflammation-related markers between women and men. Moreover, the levels of inflammatory markers were increased in the kidney diseases regardless of the age difference. CONCLUSIONS: This study showed that the physiological bioactive substances NGAL, MCP1 and CLU can be increased in renal pathologies and considered as good indicators of progression of inflammation in chronic kidney diseases, with no role of gender and age in their increment plasma levels.

Role of MCP-1 in the development of tubulointerstitial fibrosis in patients with primary chronic glomerulonephritis

BACKGROUND. To date, the study of the factors involved in the glomerular-tubular pathological connections leading to damage to the tubulointerstitial tissue is one of the topical areas of nephrology. THE AIM: to study the effect of MCP-1 in the development of tubulointerstitial fibrosis as a factor in the irreversible progression of chronic renal failure. PATIENTS ANDMETHODS. Prospective observation and retrospective analysis of case histories were carried out, which included a total of 75 patients with primary chronic glomerulonephritis. RESULTS. The average age of the patients was 36.7 ± 12.3 years, of which 52 were males, 23 were women. The average length of service in a nephrological disease was 3.0 [1.0; 5.0] years. The calculated GFR values are 87.3 ± 31.2 ml / min / 1.73 m2. In the general population, the moderate degree of MCP-1 expression, estimated at 2 points, was 35 %, pronounced expression was found in 25 % of the respondents. In the mesangium of the glomeruli and in macrophages, the expressed degree of MCP-1 expression was 20 % and 16 %, respectively, which characterizes MCP-1 as a marker produced by resident cells. When studying the relationship of MCP-1 in blood with clinical parameters, a correlation was found with the values of total protein (Rs= –0.43; p <0.05), with erythrocyturia (Rs= –0.28; p <0.05), as well as with an albumin level (Rs= –0.5; p <0.05), which indicates the role of MCP-1 in the development of nephritic forms of glomerulonephritis. Depending on the severity of MCP-1 expression in biopsy specimens, the incidence of focal tubulointerstitial fibrosis with MCP-1 expression estimated at 1 point was 13.3 %, 2 points – 14.3 %, 3 points – 44.0 %. The revealed significant correlation between the serum level of MCP-1 and the severity of tubulointerstitial fibrosis confirms the MCP-1-mediated mechanism of progression of CKD. CONCLUSION. The relationship of serum and tissue forms of MCP-1 with the progression of tubulointerstitial fibrosis in chronic glomerulonephritis has been demonstrated. MCP-1-induced mesangial cell plays a critical role in the development of renal tubular damage, and its increased expression is associated with progressive tubulointerstitial fibrosis and decreased renal function.