Role of ERK1/2 and JNK phosphorylation in iodine contrast agent-induced apoptosis in diabetic rat kidneys

Abstract

Background: The risk of contrast-induced acute kidney injury (CIAKI) is significantly increased in patients with diabetes mellitus. This study aimed to investigate molecular mechanisms of contrast media-induced apoptosis in diabetic rat kidneys, especially the involvement of ERK1/2 and JNK signal pathways. Methods: Diabetic Sprague-Dawley rats were induced by intraperitoneal injection of streptozotocin. Ten weeks later the normal and diabetic rats were administered high-osmolar contrast media (HOCM; meglumine diatrizoate) or normal saline (10 mL/kg) injection for 2 consecutive days. At 24 h after the operation, the rats were sacrificed, the blood samples were collected for examining serum creatinine and the kidneys were collected for determining the expression of caspase-3 by immunohistochemistry and the expression of Bcl-2, Bax, upstream signal molecule p-JNK, and p-ERK1/2 by western blotting. Results: The serum creatinine was significantly increased in diabetes + contrast media group (DC group) after operation compared with in the diabetic group (D group; 103.89 ± 9.01 mmol/L vs. 71.52 ± 7.03 mmol/L, p50.05). While creatinine clearance rate (Ccr) was significantly decreased in DC group after operation (1.49 ± 0.33 mL/min vs. 2.60 ± 0.54 mL/min, p50.05). Especially, in the diabetic kidney, the expression of caspase-3 was also significantly increased after intravenous injection of HOCM compared with normal saline. The expression level of upstream signal molecule p-JNK protein was apparently increased, but p-ERK1/2 protein was significantly decreased (both p50.05). Conclusions: The ionic HOCM-induced renal cells apoptosis in diabetic rats through activating the caspase-3 apoptotic pathway, which might be mediated by upstream MAPK (inhibiting p-ERK1/2 expression and promoting p-JNK expression) signal pathways.

Anti-Apoptotic and Antioxidant Effects of 3-Epi-Iso-Seco-Tanapartholide Isolated from Artemisia argyi against Iodixanol-Induced Kidney Epithelial Cell Death

“…There is evidence of similar roles of JNK and p38 and vice versa. Contrary to our findings, a previous study provides evidence for a protective role of ERK against contrast-induced nephropathy in vivo [ 45 ]. In the present study, treatment with U0126 attenuates iodixanol-induced LLC-PK1 cell death and this protective effect was synergistic when treated with 5 μM of compound 8 .…”

“…In our study, pretreatment with compound 8 inhibited the phosphorylation of ERK, JNK, and p38 induced by iodixanol. Studies have reported that JNK and p38 induced by oxidative stress regulate apoptosis against contrast-induced nephropathy in vitro and in vivo [ 44 , 45 ]. In contrast, the role of ERK remains less clear than that of JNK and p38 and remains controversial, with conflicting evidence.…”

Mitogen-Activated Protein Kinases and Hypoxic/Ischemic Nephropathy

“…For example, some studies showed that the activation of ERK1/2 signaling pathway in the human kidney with glomerulopathies correlated with cell proliferation, histologic lesions, renal fibrosis and dysfunction [33], while other work suggests that apoptosis in diabetic rat kidneys is likely related to a decrease in phosphorylated ERK1/2 levels and an increase in phosphorylated JNK levels [34]. A better understanding of renal MAPK function under hypoxic/ischemic conditions may therefore…”

Rapeseed protein-derived antioxidant peptide RAP alleviates renal fibrosis through MAPK/NF-κB signaling pathways in diabetic nephropathy

“…Previous studies have shown that phosphorylation of MAPKs is upregulated in the kidneys of STZ-induced diabetic rats. 34 Hence, we assessed the role of RAP treatment on MAPK activation by examining the phosphorylation of ERK1/2 and p38 using immunohistochemical analysis. The results showed that the positive areas of phosphorylated ERK1/2 and p38 staining were markedly increased in STZ-induced diabetic kidneys compared to normal control kidneys.…”