The Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
The Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
Aging (Albany NY). 2021 Nov 29;13(22):24605-24620. doi: 10.18632/aging.203694.
Diabetic nephropathy is a major complication of diabetes. We explore the protective effect of TRPM2 knockdown on the progression of diabetic nephropathy.
A type 2 diabetes animal model was established in C57BL/6N mice by long-term high-fat diet (HFD) feeding combined with a single injection of 100 mg/kg streptozotocin (STZ). Genetic knockdown of TRPM2 in mouse kidneys was accomplished by the intravenous injection via the tail vein of adeno-associated virus type 2 carrying TRPM2 shRNA.
Mice with HFD/STZ-induced diabetes exhibited kidney dysfunction, as demonstrated by increased blood creatinine and urea nitrogen levels, accompanied by glomerulus derangement, tubule damage and extracellular matrix deposition in the interstitium. The protein expression of TRPM2, transforming growth factor-β1 (TGF-β1), connective tissue growth factor, α-smooth muscles actin, fibronectin, collagen I and collagen III, and the mRNA expression and contents of inflammatory factors, including interleukin-1β, interleukin-6, interferon-α, tumour necrosis factor -α and monocyte chemotactic protein -1, were significantly elevated in the renal tissues of the HFD/STZ-induced diabetes group compared to those of the two control groups. Furthermore, fluorescent staining of TRPM2 was markedly increased in the renal tubular epithelial cells from diabetic mice. Knockdown of TRPM2 significantly attenuated HFD/STZ-induced renal inflammatory responses and fibrosis, which was accompanied by activation of TGF-β1-activated c-Jun N-terminal protein kinase-1 (JNK1) signalling. JNK1 inactivation reversed hyperglycaemia-induced fibrosis and inflammation in HK-2 cells.
TRPM2 silencing significantly attenuated fibrosis and inflammation in the kidneys of mice with HFD/STZ-induced diabetes, which was largely achieved via the inhibition of TGF-β1-activated JNK1 activation.
糖尿病肾病是糖尿病的主要并发症。我们探索了 TRPM2 敲低对糖尿病肾病进展的保护作用。
通过长期高脂肪饮食（HFD）喂养结合单次 100mg/kg 链脲佐菌素（STZ）注射，在 C57BL/6N 小鼠中建立 2 型糖尿病动物模型。通过尾静脉静脉内注射携带 TRPM2 shRNA 的腺相关病毒 2 型，在小鼠肾脏中实现 TRPM2 的基因敲低。
HFD/STZ 诱导的糖尿病小鼠表现出肾功能障碍，表现为血肌酐和尿素氮水平升高，同时伴有肾小球紊乱、小管损伤和间质中细胞外基质沉积。TRPM2、转化生长因子-β1（TGF-β1）、结缔组织生长因子、α-平滑肌肌动蛋白、纤连蛋白、胶原 I 和胶原 III 的蛋白表达，以及白细胞介素-1β、白细胞介素-6、干扰素-α、肿瘤坏死因子-α和单核细胞趋化蛋白-1 等炎症因子的 mRNA 表达和含量，在 HFD/STZ 诱导的糖尿病组的肾脏组织中均显著高于两组对照组。此外，糖尿病小鼠肾小管上皮细胞中 TRPM2 的荧光染色明显增加。TRPM2 敲低显著减弱了 HFD/STZ 诱导的肾脏炎症反应和纤维化，同时伴随着 TGF-β1 激活的 c-Jun N 末端蛋白激酶-1（JNK1）信号通路的激活。JNK1 失活逆转了高血糖诱导的 HK-2 细胞纤维化和炎症。
TRPM2 沉默显著减轻了 HFD/STZ 诱导的糖尿病小鼠肾脏的纤维化和炎症，这主要是通过抑制 TGF-β1 激活的 JNK1 激活来实现的。
