Fibrosis is the final common pathway leading to end stage chronic kidney disease (CKD). However, the function of protein palmitoylation in renal fibrosis and underlying mechanisms remain unclear. In this study, we observed that the expression of the palmitoyltransferase ZDHHC18 was significantly elevated in unilateral ureteral obstruction (UUO) and folic acid (FA)-induced renal fibrosis mouse models, and was significantly upregulated in the fibrotic kidneys of chronic kidney disease patients. Functionally, tubule-specific deletion of ZDHHC18 attenuated tubular epithelial cells partial epithelial-to-mesenchymal transition (EMT), then reduced production of profibrotic cytokine and alleviates tubulointerstitial fibrosis. In contrast, ZDHHC18 overexpression exacerbated progressive renal fibrosis. Mechanistically, ZDHHC18 catalyzed the palmitoylation of HRAS, which is pivotal for its translocation to the plasma membrane and subsequent activation. HRAS palmitoylation promoted downstream phosphorylation of MEK/ERK and further activated RREB1, enhancing SMAD binding to the Snai1 cis-regulatory regions. Taken together, our findings suggest that ZDHHC18 plays a crucial role in renal fibrogenesis and presents a potential therapeutic target for combating kidney fibrosis.

中文翻译：

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ZDHHC18 通过调节 HRAS 棕榈酰化促进肾纤维化的发展。


纤维化是导致终末期慢性肾脏病 （CKD） 的最后常见途径。然而，蛋白质棕榈酰化在肾纤维化中的功能及其潜在机制仍不清楚。在这项研究中，我们观察到棕榈酰转移酶 ZDHHC18 的表达在单侧输尿管梗阻 （UUO） 和叶酸 （FA） 诱导的肾纤维化小鼠模型中显著升高，在慢性肾脏病患者的纤维化肾脏中显著上调。在功能上，ZDHHC18减毒肾小管上皮细胞的部分上皮到间充质转化 （EMT） 的小管特异性缺失，然后减少了促纤维化细胞因子的产生并减轻了肾小管间质纤维化。相比之下，ZDHHC18过表达加剧了进行性肾纤维化。从机制上讲，ZDHHC18催化了 HRAS 的棕榈酰化，这对于其转位到质膜和随后的激活至关重要。HRAS 棕榈酰化促进 MEK/ERK 的下游磷酸化并进一步激活 RREB1，增强 SMAD 与 Snai1 顺式调节区域的结合。综上所述，我们的研究结果表明，ZDHHC18 在肾纤维化中起着至关重要的作用，并提出了对抗肾纤维化的潜在治疗靶点。