Restoration of kidney tubular epithelium following sub-lethal injury sequentially involves partial-epithelial-mesenchymal transition (pEMT), proliferation and further re-differentiation into specialized tubule epithelial cells (TECs). Since the immunosuppressant cyclosporine-A produces pEMT in TECs and inhibits the peptidyl-prolyl isomerase (PPIase) activity of cyclophilin (Cyp) proteins, we hypothesized that cyclophilins could regulate TEC phenotype. Here we demonstrate that in cultured TECs, CypA silencing triggers loss of epithelial features and enhances TGFβ-induced EMT in association with up-regulation of epithelial repressors Slug and Snail. This pro-epithelial action of CypA relies on its PPIase activity. By contrast, CypB emerges as an epithelial repressor, since CypB silencing promotes epithelial differentiation, prevents TGFβ-induced EMT, and induces tubular structures in 3D cultures. In addition, in the kidneys of CypB knockout mice subjected to unilateral ureteral obstruction (UUO), inflammatory and pro-fibrotic events were attenuated. CypB silencing/knockout leads to Slug, but not Snail, down-regulation. CypB’s support of Slug expression depends on its endoplasmic reticulum location, where it interacts with calreticulin, a calcium-buffering chaperone related to Slug expression. Since CypB silencing reduces ionomycin-induced calcium release and Slug up-regulation, we suggest that Slug expression may rely on CypB modulation of calreticulin-dependent calcium signaling. In conclusion, this work uncovers new roles for CypA and CypB in modulating TECs plasticity and identifies CypB as a druggable target potentially relevant in promoting kidney repair.

中文翻译：

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亲环蛋白 A 和 B 反向调节肾小管上皮细胞表型。

亚致死损伤后肾小管上皮的恢复依次涉及部分上皮间质转化 (pEMT)、增殖和进一步再分化为特化的小管上皮细胞 (TEC)。由于免疫抑制剂环孢菌素-A 在 TEC 中产生 pEMT 并抑制亲环蛋白 (Cyp) 蛋白的肽基-脯氨酰异构酶 (PPIase) 活性，我们假设亲环蛋白可以调节 TEC 表型。在这里，我们证明在培养的 TECs 中，CypA 沉默触发上皮特征的丧失并增强 TGFβ 诱导的 EMT，并与上皮抑制因子 Slug 和 Snail 的上调相关。CypA 的这种促上皮作用依赖于其 PPIase 活性。相比之下，CypB 作为上皮阻遏物出现，因为 CypB 沉默促进上皮分化，防止 TGFβ 诱导的 EMT，并在 3D 培养物中诱导管状结构。此外，在遭受单侧输尿管梗阻 (UUO) 的 CypB 基因敲除小鼠的肾脏中，炎症和促纤维化事件减弱。CypB 沉默/敲除导致 Slug 而不是 Snail 下调。CypB 对 Slug 表达的支持取决于其内质网的位置，在那里它与钙网蛋白相互作用，钙网蛋白是一种与 Slug 表达相关的钙缓冲伴侣。由于 CypB 沉默减少了离子霉素诱导的钙释放和 Slug 上调，我们认为 Slug 表达可能依赖于 CypB 对钙网蛋白依赖性钙信号传导的调节。总之，这项工作揭示了 CypA 和 CypB 在调节 TEC 可塑性方面的新作用，并将 CypB 确定为可能与促进肾脏修复相关的药物靶点。