Tubulointerstitial inflammation is crucial for the progression of diabetic nephropathy (DN), and tubular cells act as a driving force in the inflammatory cascade. Emerging data suggested that tacrolimus (TAC) ameliorates podocyte injury and macrophage infiltration in streptozotocin (STZ) mice. However, the effect of TAC on tubulointerstitial inflammation remains unknown. We found that albuminuria and tubulointerstitial damage improved in db/db mice treated with TAC. Macrophage infiltration and expression of IL‐6, TNF‐α, fibronectin, collagen 1 and cleaved caspase 3 were inhibited as well. In addition, the expression of nuclear factor of activated T cell 1 (NFATc1) and transient receptor potential channel 6 (TRPC6) was up‐regulated in the kidneys of DN patients and correlated with tubular injury and inflammation. The expression of NFATc1 and TRPC6 also increased in the kidneys of db/db mice and HK‐2 cells with high glucose (HG), while TAC inhibited these effects. HG‐induced inflammatory markers and apoptosis were reversed by TAC and NFATc1 siRNA in HK‐2 cells, which was abolished by TRPC6 plasmid. Furthermore, HG‐induced TRPC6 expression was inhibited by NFATc1 siRNA, while NFATc1 nuclear translocation was inhibited by TAC, but was restored by TRPC6 plasmid in HK‐2 cells under HG conditions. These findings suggest that TAC ameliorates tubulointerstitial inflammation in DN through NFATc1/TRPC6 feedback loop.

中文翻译：

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他克莫司通过抑制 NFATc1/TRPC6 通路改善糖尿病肾病的肾小管间质炎症。

肾小管间质炎症对于糖尿病肾病 (DN) 的进展至关重要，而肾小管细胞在炎症级联反应中起着驱动力的作用。新出现的数据表明，他克莫司 (TAC) 可改善链脲佐菌素 (STZ) 小鼠的足细胞损伤和巨噬细胞浸润。然而，TAC 对肾小管间质炎症的影响仍然未知。我们发现用 TAC 治疗的 db/db 小鼠的蛋白尿和肾小管间质损伤有所改善。巨噬细胞浸润和 IL-6、TNF-α、纤连蛋白、胶原蛋白 1 和裂解的半胱天冬酶 3 的表达也受到抑制。此外，DN 患者肾脏中活化 T 细胞核因子 1 (NFATc1) 和瞬时受体电位通道 6 (TRPC6) 的表达上调，并与肾小管损伤和炎症相关。NFATc1 和 TRPC6 在 db/db 小鼠肾脏和高糖 (HG) HK-2 细胞中的表达也增加，而 TAC 抑制这些作用。HG 诱导的炎症标志物和细胞凋亡在 HK-2 细胞中被 TAC 和 NFATc1 siRNA 逆转，这被 TRPC6 质粒消除。此外，HG 诱导的 TRPC6 表达被 NFATc1 siRNA 抑制，而 NFATc1 核易位被 TAC 抑制，但在 HG 条件下在 HK-2 细胞中被 TRPC6 质粒恢复。这些发现表明 TAC 通过 NFATc1/TRPC6 反馈回路改善 DN 中的小管间质炎症。此外，HG 诱导的 TRPC6 表达被 NFATc1 siRNA 抑制，而 NFATc1 核易位被 TAC 抑制，但在 HG 条件下在 HK-2 细胞中被 TRPC6 质粒恢复。这些发现表明 TAC 通过 NFATc1/TRPC6 反馈回路改善 DN 中的小管间质炎症。此外，HG 诱导的 TRPC6 表达被 NFATc1 siRNA 抑制，而 NFATc1 核易位被 TAC 抑制，但在 HG 条件下在 HK-2 细胞中被 TRPC6 质粒恢复。这些发现表明 TAC 通过 NFATc1/TRPC6 反馈回路改善 DN 中的小管间质炎症。