Al-Tantawy Samar M, Eraky Salma M, Eissa Laila A
Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Dec 19. doi: 10.1007/s00210-024-03669-5.
One of the most common microvascular effects of diabetes mellitus (DM) that may result in end-stage renal failure is diabetic kidney disease (DKD). Current treatments carry a substantial residual risk of disease progression regardless of treatment. By modulating various molecular targets, pentacyclic triterpenoid celastrol has been found to possess curative properties in the treatment of diabetes and other inflammatory diseases. Therefore, the present study investigated whether celastrol has anti-inflammatory, antioxidant, and antifibrotic effects as a natural compound against experimental DKD. Streptozotocin (55 mg/kg) was utilized for inducing DKD in a rat model. Antioxidant enzymes and renal function tests were assessed in serum samples. In kidney homogenate, relative miRNA-192-5p and miRNA-21-5p gene expressions were measured. Furthermore, using real-time PCR to evaluate the gene expressions of nucleus erythroid 2-related factor-2 (Nrf-2), matrix metalloproteinase-2 (MMP-2), proapoptotic caspase-3, antiapoptotic Bcl-2, LC-3, and Beclin-1. Moreover, the transforming growth factor β1 (TGF-β1), LC-3, Bcl-2, caspase-3 and NADPH oxidase 4 (NOX4) renal expressions were assessed semi-quantitatively using immunohistochemistry. Seven weeks of celastrol (1.5 mg/kg/day) treatment significantly ameliorated DKD. Celastrol improves kidney functions. Moreover, celastrol treatment demonstrated potent antioxidant effect. The mechanism of apoptosis resulting from the administration of celastrol included the modulation of Bcl-2 and caspase-3 expression in the kidney. Celasterol administration leads to an increase in LC-3 and Beclin-1 renal expression that resulting in autophagy. Celastrol treatment improved renal fibrosis by decreasing TGF-β1 and MMP-2 renal expression. These antifibrotic effects could be due to their ability to inhibit miRNA-192-5p and miRNA-21-5p expression in renal tissues. Celastrol exerts a renoprotective effect by targeting miRNA-21 and miRNA-192, as well as their downstream pathways, such as autophagy, apoptosis, and fibrosis.
糖尿病（DM）最常见的微血管效应之一是糖尿病肾病（DKD），它可能导致终末期肾衰竭。目前的治疗方法无论采用何种治疗手段，都存在疾病进展的显著残余风险。五环三萜类化合物雷公藤红素通过调节各种分子靶点，已被发现具有治疗糖尿病和其他炎症性疾病的特性。因此，本研究调查了雷公藤红素作为一种天然化合物，对实验性DKD是否具有抗炎、抗氧化和抗纤维化作用。采用链脲佐菌素（55mg/kg）诱导大鼠模型产生DKD。评估血清样本中的抗氧化酶和肾功能测试。在肾匀浆中，测量相对miRNA-192-5p和miRNA-21-5p基因表达。此外，使用实时PCR评估细胞核红细胞2相关因子2（Nrf-2）、基质金属蛋白酶2（MMP-2）、促凋亡半胱天冬酶3、抗凋亡Bcl-2、LC-3和Beclin-1的基因表达。此外，采用免疫组织化学半定量评估转化生长因子β1（TGF-β1）、LC-3、Bcl-2、半胱天冬酶3和NADPH氧化酶4（NOX4）的肾脏表达。雷公藤红素（1.5mg/kg/天）治疗7周显著改善了DKD。雷公藤红素改善了肾功能。此外，雷公藤红素治疗显示出强大的抗氧化作用。雷公藤红素给药导致的凋亡机制包括调节肾脏中Bcl-2和半胱天冬酶3的表达。给予雷公藤红素导致肾脏中LC-3和Beclin-1表达增加，从而导致自噬。雷公藤红素治疗通过降低肾脏中TGF-β1和MMP-2的表达改善了肾纤维化。这些抗纤维化作用可能归因于它们抑制肾组织中miRNA-192-5p和miRNA-21-5p表达的能力。雷公藤红素通过靶向miRNA-21和miRNA-192及其下游途径（如自噬、凋亡和纤维化）发挥肾脏保护作用。
