Renal fibrosis is characterized by chronic inflammation and excessive accumulation of extracellular matrix and progressively leads to functional insufficiency and even total loss of kidney function. In this study we investigated the anti-fibrotic potential of two highly selective and potent SK2 inhibitors, SLM6031434 and HWG-35D, in unilateral ureter obstruction (UUO), a model for progressive renal fibrosis, in mice. In both cases, treatment with SLM6031434 or HWG-35D resulted in an attenuated fibrotic response to UUO in comparison to vehicle-treated mice as demonstrated by reduced collagen accumulation and a decreased expression of collagen-1 (Col1), fibronectin-1 (FN-1), connective tissue growth factor (CTGF), and α-smooth muscle actin (α-SMA). Similar to our previous study in Sphk2^−/− mice, we found an increased protein expression of Smad7, a negative regulator of the pro-fibrotic TGFβ/Smad signalling cascade, accompanied by a strong accumulation of sphingosine in SK2 inhibitor-treated kidneys. Treatment of primary renal fibroblasts with SLM6031434 or HWG-35D dose-dependently increased Smad7 expression and ameliorated the expression of Col1, FN-1 and CTGF.

In summary, these data prove the anti-fibrotic potential of SK2 inhibition in a mouse model of renal fibrosis, thereby validating SK2 as pharmacological target for the treatment of fibrosis in chronic kidney disease.

肾纤维化的特征是慢性炎症和细胞外基质的过度积累，并逐渐导致功能不全，甚至肾功能完全丧失。在这项研究中，我们研究了两种高选择性和强效 SK2 抑制剂 SLM6031434 和 HWG-35D 在小鼠进行性肾纤维化模型单侧输尿管阻塞 (UUO) 中的抗纤维化潜力。在这两种情况下，与载体处理的小鼠相比，用 SLM6031434 或 HWG-35D 处理导致对 UUO 的纤维化反应减弱，如胶原蛋白积累减少和胶原蛋白-1 (Col1)、纤连蛋白-1 (FN- 1）、结缔组织生长因子（CTGF）和α-平滑肌肌动蛋白（α-SMA）。类似于我们之前在Sphk2 中的研究^-/-在小鼠中，我们发现 Smad7 的蛋白质表达增加，Smad7 是促纤维化 TGFβ/Smad 信号级联的负调节因子，伴随着 SK2 抑制剂处理的肾脏中鞘氨醇的强烈积累。用 SLM6031434 或 HWG-35D 处理原代肾成纤维细胞剂量依赖性地增加 Smad7 表达并改善 Col1、FN-1 和 CTGF 的表达。

总之，这些数据证明了 SK2 抑制在肾纤维化小鼠模型中的抗纤维化潜力，从而验证了 SK2 作为治疗慢性肾病纤维化的药理学靶点。