Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Science, 2019RU066, Lanzhou University, Lanzhou, China.
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Science, 2019RU066, Lanzhou University, Lanzhou, China
J Pharmacol Exp Ther. 2023 Sep;386(3):310-322. doi: 10.1124/jpet.123.001621. Epub 2023 Jul 7.
Renal fibrosis is characterized by the excessive deposition of extracellular matrix that destroys and replaces the functional renal parenchyma, ultimately leading to organ failure. It is a common pathway by which chronic kidney disease can develop into end-stage renal disease, which has high global morbidity and mortality, and there are currently no good therapeutic agents available. Calcium/calmodulin-dependent protein kinase II (CaMKII) has been indicated to be closely related to the occurrence of renal fibrosis, and its specific inhibitory peptide, autocamtide-2-related inhibitory peptide (AIP), was shown to directly bind the active site of CaMKII. In this study, we examined the effect of AIP on the progression of renal fibrosis and its possible mechanism. The results showed that AIP could inhibit the expression of the fibrosis markers fibronectin, collagen I, matrix metalloproteinase 2, and -smooth muscle actin in vivo and in vitro. Further analysis revealed that AIP could inhibit the expression of various epithelial-to-mesenchymal transformation-related markers, such as vimentin and Snail 1, in vivo and in vitro. Mechanistically, AIP could significantly inhibit the activation of CaMKII, Smad 2, Raf, and extracellular regulated protein kinases (ERK) in vitro and in vivo and reduce the expression of transforming growth factor- (TGF-) in vivo. These results suggested that AIP could alleviate renal fibrosis by inhibiting CaMKII and blocking activation of the TGF-/Smad2 and RAF/ERK pathways. Our study provides a possible drug candidate and demonstrates that CaMKII is a potential pharmacological target for the treatment of renal fibrosis. SIGNIFICANCE STATEMENT: We have demonstrated that AIP significantly attenuated transforming growth factor--1-induced fibrogenesis and ameliorated unilateral ureteral obstruction-induced renal fibrosis through the CaMKII/TGF-β/Smad and CaMKII/RAF/ERK signaling pathways in vitro and in vivo. Our study provides a possible drug candidate and demonstrates that CaMKII can be a potential pharmacological target for the treatment of renal fibrosis.
肾纤维化的特征是细胞外基质的过度沉积，破坏和取代功能性肾实质，最终导致器官衰竭。它是慢性肾脏病发展为终末期肾病的常见途径，这种疾病具有很高的全球发病率和死亡率，目前尚无有效的治疗药物。钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）已被证明与肾纤维化的发生密切相关，其特异性抑制肽，自磷酸化肽（AIP），被证明可以直接结合 CaMKII 的活性位点。在这项研究中，我们研究了 AIP 对肾纤维化进展的影响及其可能的机制。结果表明，AIP 可以抑制体内和体外纤维化标志物纤连蛋白、胶原 I、基质金属蛋白酶 2 和 -平滑肌肌动蛋白的表达。进一步分析表明，AIP 可以抑制体内和体外各种上皮间质转化相关标志物，如波形蛋白和 Snail 1 的表达。在机制上，AIP 可以显著抑制体内和体外 CaMKII、Smad 2、Raf 和细胞外调节蛋白激酶（ERK）的激活，并减少体内转化生长因子-（TGF-）的表达。这些结果表明，AIP 可以通过抑制 CaMKII 并阻断 TGF-/Smad2 和 RAF/ERK 通路的激活来减轻肾纤维化。我们的研究为治疗肾纤维化提供了一种可能的药物候选物，并证明 CaMKII 是治疗肾纤维化的潜在药物靶点。
