This study investigated if the nephroprotective effect of Curcumin in streptozotocin-induced type 1 diabetes mellitus (DM) in rats involves downregulation/inhibition of p⁶⁶Shc and examined the underlying mechanisms. Rats were divided into 4 groups (n = 12/group) as control, control + Curcumin (100 mg/kg), T1DM, and T1DM + Curcumin. Curcumin was administered orally to control or diabetic rats for 12 weeks daily. As compared to diabetic rats, Curcumin didn't affect either plasma glucose or insulin levels but significantly reduced serum levels of urea, blood urea nitrogen, and creatinine, and concurrently reduced albumin/protein urea and increased creatinine clearance. It also prevented the damage in renal tubules and mitochondria, mesangial cell expansion, the thickness of the basement membrane. Mechanistically, Curcumin reduced mRNA and protein levels of collagen I/III and transforming growth factor- β-1 (TGF-β1), reduced inflammatory cytokines levels, improved markers of mitochondrial function, and suppressed the release of cytochrome-c and the activation of caspase-3. In the kidneys of both control and diabetic rats, Curcumin reduced the levels of reactive oxygen species (ROS), increased mRNA levels of manganese superoxide dismutase (MnSOD) and gamma-glutamyl ligase, increased glutathione (GSH) and protein levels of Bcl-2 and MnSOD, and increased the nuclear levels of nuclear factor2 (Nrf2) and FOXO-3a. Besides, Curcumin reduced the nuclear activity of the nuclear factor-kappa B (NF-κB), downregulated protein kinase CβII (PKCβII), NADPH oxidase, and p⁶⁶Shc, and decreased the activation of p⁶⁶Shc. In conclusion, Curcumin prevents kidney damage in diabetic rats by activating Nrf2, inhibiting Nf-κB, suppressing NADPH oxidase, and downregulating/inhibiting PKCβII/p⁶⁶Shc axis.

本研究调查了姜黄素对链脲佐菌素诱导的 1 型糖尿病 (DM) 大鼠的肾脏保护作用是否涉及 p ⁶⁶ Shc 的下调/抑制，并检查了潜在的机制。将大鼠分为 4 组（n = 12/组）作为对照、对照 + 姜黄素 (100 mg/kg)、T1DM 和 T1DM + 姜黄素。姜黄素每天口服给予对照或糖尿病大鼠 12 周。与糖尿病大鼠相比，姜黄素不影响血浆葡萄糖或胰岛素水平，但显着降低血清尿素、尿素氮和肌酐水平，同时降低白蛋白/蛋白尿素和增加肌酐清除率。它还可以防止肾小管和线粒体的损​​伤、系膜细胞的扩张、基底膜的厚度。从机制上讲，姜黄素降低了胶原蛋白 I/III 和转化生长因子-β-1 (TGF-β1) 的 mRNA 和蛋白质水平，降低了炎性细胞因子水平，改善了线粒体功能的标志物，并抑制了细胞色素 C 的释放和激活caspase-3。在对照组和糖尿病大鼠的肾脏中，姜黄素降低了活性氧 (ROS) 的水平，增加了锰超氧化物歧化酶 (MnSOD) 和 γ-谷氨酰连接酶的 mRNA 水平，增加了谷胱甘肽 (GSH) 和 Bcl-2 的蛋白质水平和 MnSOD，并增加核因子 2 (Nrf2) 和 FOXO-3a 的核水平。此外，姜黄素降低核因子-κB (NF-κB)、下调蛋白激酶 CβII (PKCβII)、NADPH 氧化酶和 p⁶⁶ Shc，并降低 p ⁶⁶ Shc的活化。总之，姜黄素通过激活 Nrf2、抑制 Nf-κB、抑制 NADPH 氧化酶和下调/抑制 PKCβII/p ⁶⁶ Shc 轴来预防糖尿病大鼠的肾损伤。