Ulinastatin ameliorated streptozotocin-induced diabetic nephropathy: Potential effects via modulating the components of gut-kidney axis and restoring mitochondrial homeostasis.

Growing evidence supports the role of the gut-kidney axis and persistent mitochondrial dysfunction in the pathogenesis of diabetic nephropathy (DN). Ulinastatin (UTI) has a potent anti-inflammatory effect, protecting the kidney and the gut barrier in sepsis, but its effect on DN has yet to be investigated. This study aimed to assess the potential mitigating effect of UTI on DN and investigate the possible involvement of gut-kidney axis and mitochondrial homeostasis in this effect. Forty male Wistar rats were divided equally into four groups: normal; UTI-treated control; untreated DN; and UTI-treated DN. At the end of the experiment, UTI ameliorated DN by modulating the gut-kidney axis as it improved serum and urinary creatinine, urine volume, creatinine clearance, blood urea nitrogen, urinary albumin, intestinal morphology including villus height, crypt depth, and number of goblet cells, with upregulating the expression of intestinal tight-junction protein claudin-1, and counteracting kidney changes as indicated by significantly decreasing glomerular tuft area and periglomerular and peritubular collagen deposition. In addition, it significantly reduced intestinal and renal nuclear factor kappa B (NF-κB), serum Complement 5a (C5a), renal monocyte chemoattractant protein-1 (MCP-1), renal intercellular adhesion molecule 1 (ICAM1), and renal signal transducer and activator of transcription 3 (STAT3), mitochondrial dynamin related protein 1 (Drp1), mitochondrial fission 1 protein (FIS1), mitochondrial reactive oxygen species (ROS), renal hydrogen peroxide (H2O2), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels. Furthermore, it significantly increased serum short chain fatty acids (SCFAs), and mitochondrial ATP levels and mitochondrial transmembrane potential. Moreover, there were significant correlations between measured markers of gut components of the gut-kidney axis and renal function tests in UTI-treated DN group. In conclusion, UTI has a promising therapeutic effect on DN by modulating the gut-kidney axis and improving renal mitochondrial dynamics and redox equilibrium.

Association of Serum Osteoprotegerin Level With Myocardial Injury and Cardiovascular Calcification in Chronic Kidney Disease Patients.

Background: Chronic kidney disease has emerged as a significant independent risk factor for cardiovascular disease. Cardiovascular calcification is an active process involving a complex interaction of inducers and inhibitors. High sensitivity cardiac troponin T assay detects troponin T with higher sensitivity and precision at an earlier point of time than the conventional assays, and is associated with poor outcomes. Serum osteoprotegerin is classed as an inhibitory factor for cardiovascular calcification. It is involved in the pathological processes of vascular damage and linked to the excess cardiovascular morbidity. The aim of the present study was to evaluate the extent of cardiovascular calcification and serum high sensitivity cardiac troponin T level, and their association with serum osteoprotegerin level in patients with chronic kidney disease stages 3-5. Methods: 90 chronic kidney disease patients were enrolled in this study, and they were divided into two groups: group (1) included 45 non-dialysis-dependent chronic kidney disease patients (stages 3-5) and group (2) included 45 chronic hemodialysis patients. Each group further subdivided according to the presence of cardiovascular calcification into subgroup A and B. Vascular calcifications were assessed by lateral lumbar, pelvis and hands X-ray radiographs. Valvular calcification was assessed by echocardiography. Serum cardiac troponin T was measured by high sensitivity assay and serum osteoprotegerin was measured by ELISA. Results: Cardiovascular calcification distribution was 22.2% in group (1) and 33.3% in group (2). Serum osteoprotegerin and troponin T in calcification groups (1A and 2A) were significantly higher than non-calcification groups (1B and 2B; P < 0.001). Osteoprotegerin correlated positively with high sensitivity cardiac troponin T (rs = 0.72, P < 0.001). cardiovascular calcification correlated positively with osteoprotegerin, troponin T, and phosphorus. osteoprotegerin and phosphorus were significant independent predictors of cardiovascular calcification at cut-off values ≥4.6 ng/L and ≥6.95 mg/dl, respectively (P < 0.001). Serum phosphorus and creatinine were independent predictors of osteoprotegerin (P < 0.001 and 0.048, respectively). Conclusion: Osteoprotegerin is strongly associated with cardiovascular calcification and high sensitivity cardiac troponin T. In addition, there is a positive association between calcification and troponin T. This suggests a role for osteoprotegerin in the pathogenesis and risk stratification of cardiovascular calcification and myocardial injury in chronic kidney disease patients with a potential role as a therapeutic target.