Correlation Between Endothelial Dysfunction and Left Ventricular Remodeling in Patients with Chronic Kidney Disease

Background/Aims: To investigate the role of endothelial dysfunction on left ventricular remodeling in patients with chronic kidney disease and to evaluate the correlation between endothelial dysfunction and left ventricular remodeling. Methods: Seventy-three patients with chronic kidney disease as study-group and thirty healthy volunteers as control-group were enrolled in the present study. All patients in both groups had echocardiography examination. The concentration of endothelin-1, nitric oxide, and inducible nitric oxide synthase of serum of all patients and healthy volunteers was measured. The incidence of cardiac structural abnormalities in patients with chronic kidney disease, and the relationship between endothelial dysfunction and cardiac structural abnormalities were analyzed. Results: The incidence of left ventricular hypertrophy, left ventricular concentric remodeling, and left ventricular systolic dysfunction was 65%, 8.33%, and 16.67%, respectively. The level of endothelin-1 and nitric oxide increased in study-group, and the concentration of inducible nitric oxide synthase decreased. There was significant positively relationship between plasma endothelin-1 and left ventricular mass index, interventricular septal thickness, left ventricular diastolic diameter. There was negatively relationship between the level of serum nitric oxide and the maximum flow velocity at the mitral in left ventricular diastolic stage. There was not any correlation between inducible nitric oxide synthase with left ventricular remodeling. Conclusions: The results showed that there was a higher incidence of left ventricular hypertrophy in patients with chronic kidney disease. Endothelin-1 and nitric oxide played an important role on the development of left ventricular hypertrophy. i 2014 S. Karger AG, Base

Tim-3 aggravates podocyte injury in diabetic nephropathy by promoting macrophage activation via the NF-κB/TNF-α pathway

Objective: Macrophage-mediated inflammation plays a significant role in the development and progression of diabetic nephropathy (DN). However, the underlying mechanisms remain unclear. Studies suggest that T cell immunoglobulin domain and mucin domain-3 (Tim-3) has complicated roles in regulating macrophage activation, but its roles in the progression of DN are still completely unknown. Methods: We downregulated Tim-3 expression in kidney (intrarenal injection of Tim-3 shRNA expressing lentivirus or global Tim-3 knockout mice) and induced DN by streptozotocin (STZ). We analyzed the degree of renal injury, especially the podocyte injury induced by activated macrophages in vitro and in vivo. Then, we transferred different bone marrow derived macrophages (BMs) into STZ-induced Tim-3 knockdown mice to examine the effects of Tim-3 on macrophages in DN. Results: First, we found that Tim-3 expression on renal macrophages was increased in patients with DN and in two diabetic mouse models, i.e. STZ-induced diabetic mice and db/db mice, and positively correlated with renal dysfunction of DN patients. Tim-3 deficiency ameliorated renal damage in STZ-induced diabetes with concurrent increase in protein levels of Nephrin and WT-1. Similar effects were observed in mice with Tim-3 knockdown diabetic mice. Second, adoptive transfer of Tim-3-expressing macrophages, but not Tim-3 knockout macrophages, accelerated diabetic renal injury in DN mice, suggesting a key role for Tim-3 on macrophages in the development of DN. Furthermore, we found NF-κB activation and TNF-α excretion were upregulated by Tim-3 in diabetic kidneys, and podocyte injury was associated with the Tim-3-mediated activation of the NF-κB/TNF-α signaling pathway in DN macrophages both in vivo and in vitro. Conclusions: These results suggest that Tim-3 functions as a key regulator in renal inflammatory processes and serves as a potential therapeutic target for renal injury in DN. Keywords: Diabetic nephropathy, Tim-3, Macrophage, NF-κB, TNF-