CXCR3 knockdown protects against high glucose-induced podocyte apoptosis and inflammatory cytokine production at the onset of diabetic nephropathy
نویسندگان
چکیده
Chemokines and their receptors play an important role in the pathogenesis of acute and chronic diabetic nephropathy (DN). However, their expression pattern and function in glomerular podocytes have not been investigated as of yet. In the present study, we investigated whether CXCR3 could protect podocytes from high glucoseinduced apoptosis and inflammatory cytokine production and explored the possible mechanism. Cell viability, cell cycle and apoptosis were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry, respectively. The level of intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (∆Ψm) was measured using a dichlorofluorescein diacetate (DCFH-DA) ortetrechloro-tetraethylbenzimidazol carbocyanine iodide (JC-1) fluorescent probe, respectively. Quantitative real-time PCR was used to determine the gene expression of CXCR3. Western blots were carried out for the related protein expression in podocytes, including CXCR3, Nephrin, Podocin, Bcl-2, Bax, and Caspase-3. Firstly, we found that CXCR3 expression was significantly upregulated and cell viability was decreased in high glucose (HG)-treated mouse podocytes in a dose-dependent manner. Secondly, knockdown of CXCR3 in mouse podocytes significantly suppressed HG-induced viability decrease, cell cycle arrest, ROS generation and ∆Ψm reduction. Moreover, knockdown of CXCR3 reduced the podocytes injury in cell apoptosis and inflammation through increasing the expression of Nephrin, Podocin and Bcl-2, and decreasing the expression of Bax and Caspase-3. In conclusion, CXCR3 knockdown protected podocytes from HG-induced apoptosis and inflammation in vitro, suggesting that inhibition of CXCR3 may have a therapeutic potential in DN treatment.
منابع مشابه
Protein S Protects against Podocyte Injury in Diabetic Nephropathy.
Background Diabetic nephropathy (DN) is a leading cause of ESRD in the United States, but the molecular mechanisms mediating the early stages of DN are unclear.Methods To assess global changes that occur in early diabetic kidneys and to identify proteins potentially involved in pathogenic pathways in DN progression, we performed proteomic analysis of diabetic and nondiabetic rat glomeruli. Prot...
متن کاملGlucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy.
Diabetic nephropathy is the most common cause of end-stage renal disease in the U.S. Recent studies demonstrate that loss of podocytes is an early feature of diabetic nephropathy that predicts its progressive course. Cause and consequences of podocyte loss during early diabetic nephropathy remain poorly understood. Here, we demonstrate that podocyte apoptosis increased sharply with onset of hyp...
متن کاملSilencing of Histone Deacetylase 9 Expression in Podocytes Attenuates Kidney Injury in Diabetic Nephropathy
Podocyte dysfunction is important in the onset and development of diabetic nephropathy (DN). Histone deacetylases (HDACs) have been recently proved to play critical roles in the pathogenesis of DN. As one subtype of the class IIa HDACs, HDAC9 is capable to repress/de-repress their target genes in tumor, inflammation, atherosclerosis and metabolic diseases. In the present study, we investigate w...
متن کاملResveratrol protects podocytes against apoptosis via stimulation of autophagy in a mouse model of diabetic nephropathy
Podocyte apoptosis coincides with albuminuria onset and precedes podocytopenia in diabetic nephropathy. However, there is a lack of effective therapeutic drugs to protect podocytes from apoptosis. Here, we demonstrated that resveratrol relieved a series of indicators of diabetic nephropathy and attenuated apoptosis of podocytes in db/db diabetic model mice. In addition, resveratrol induced auto...
متن کاملEmpagliflozin alleviates renal inflammation and oxidative stress in streptozotocin-induced diabetic rats partly by repressing HMGB1-TLR4 receptor axis
Objective(s): Empagliflozin, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, possesses verified anti-inflammatory and anti-oxidative stress effects against diabetic nephropathy. The present investigation aims to examine empagliflozin effects on the renal levels of high mobility group box-1 (HMGB1), a potent inflammatory cytokine, and its respective receptor toll-like receptor-4 (TLR-4) in ...
متن کامل