Inhibitory Effect Of Valsartan On The Endoplasmic Reticulum Stress And Inflammation In The Kidney Of Diabetic Rats

Objective : As one of the most serious microvascular complications in diabetes,Diabetic nephropathy(DN) has become the second factor leading to end-stage renal disease at present, the incidence of DN is rising year by year. The view that DN is a chronic inflammatory disease has been recognized widely, recently. But the cause of the inflammation reaction is not clear. Endoplasmic reticulum stress( ERS) has been proved to be closely associated with inflammation, and may play an important role in inflammation of the DN. In this experiment, the diabetic rat model was built to study the role of endoplasmic reticulum stress and related inflammation in kidney damage of diabetic rats and the effect of Valsartan.Methods: 34 healthy male SD rats were randomly divided into control group(Con group, n = 10), model group(DM group, n = 12) and valsartan treatment group(DM +V group, n = 12). The rats of DM group and the DM+V group were intraperitoneally injected STZ(40mg/kg) for diabete animal model. Valsartan(10mg/kg) was administered daily by gavage from the next day of the induction to diabetic rat for 6weeks. The rats of DM+V group were intragastrically administered with valsartan(10mg/kg) every day, while Con and DM group were only given the equivalent distilled water for 6 weeks.After the experiment, the weight of the rats and kidney were measured.The expression and distribution of ERS related protein GRP78 and Monocyte chemotactic protein-1(MCP-1) was examined by immunohistochemistry,The expression of ERS related protein P-IRE1α, P-JNK, JNK, NF-κB p65, P-NF-κB p65 was examined by Western blot. Real-time fluorescence quantitative PCR was used to detect the m RNA expressions of JNK, NF-κB and MCP-1, TNFα, IL-1β. 24 hour urine protein excretion, plasma albumin, Scr, BUN were checked meanwhile.Results: ① compared with Con group, 24 hours urinary protein, BUN, Scr of DM group rats were increased significantly(P< 0.05), ALB decreased(P < 0.05) compared with DM group, 24 hours urinary protein, BUN of DM+V group decreased significantly(P < 0.05), ALB increased significantly(P < 0.05), Scr reduced in the DM group,but without statistical significance(P > 0.05); ② Glomerular and tubular in Con group had no significant changes, we found that glomerular extracellular matrix hyperplasia,mesangial matrix markedly increased, basement membrane thicken,mesangium gap widened, renal tubular epithelial vacuoles degeneration with partial stove atrophy, mild interstitial edema, glomerular and interstitial inflammatory cell infiltration in the DM group. compared with DM group, DM+V group appeared the reduction of mesangial cell proliferation, renal tubular epithelial vacuoles degeneration; ③ immunohistochemical appeared that GRP78 was expressed mildly,no expression was found in MCP-1 in the Con group, the expression of MCP-1increased significantly, and strong positive expression in renal tubular epithelial cells,compared with Con group(P<0.05). DM + V group appeared that expression of GRP78,MCP-1 decreased significantly,compared with DM group(P<0.05); ④ Western blot method showed compared with Con group, the expression of P-IRE1α、P-JNK、P-NF-κB p65 was increased significantly in DM group(P < 0.05), compared with DM group,expression of P-IRE1α, P-JNK, P-NF-κB p65 was significantly decreased in DM+V group(P < 0.05), and expression of P-IRE1α, P-JNK, P-NF-κB p65 were positively correlated(P< 0.05); q RT- PCR showed that compared with Con group, the m RNA expression of MCP-1, IL-1β, NF-κB p65, TNFα increased significantly in DM group(P < 0.05),compared with DM group, the m RNA expression of MCP-1, IL-1β, NF-κB p65,TNFαdecreased significantly in DM group(P < 0.05), While there is no significant difference in the expression of JNK m RNA among three groups(P > 0.05).Conclusion: ① ERS and related inflammation was activated in the kidney of DM rats,and the activative membrane protein P-IRE1α can cause inflammation by activating JNK and NF-κB inflammatory signaling pathways; ②ANGII receptor antagonist valsartan may inhibit JNK and NF-κB signaling pathway mediated by membrane protein IRE1α to reduce inflammation and proteinuria, in addition to the factors of influencing the hemodynamics.