Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.
J Cell Mol Med. 2020 Sep;24(17):9810-9824. doi: 10.1111/jcmm.15562. Epub 2020 Aug 11.
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.
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驱动作用。新出现的数据表明，他克莫司（TAC）可改善链脲佐菌素（STZ）诱导的小鼠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尚不清楚。我们发现 TAC 治疗可改善 db/db 小鼠的蛋白尿和肾小管间质损伤。巨噬细胞浸润和 IL-6、TNF-α、纤维连接蛋白、胶原 1 和 cleaved caspase 3 的表达也受到抑制。此外，DN 患者肾脏中核因子活化 T 细胞 1（NFATc1）和瞬时受体电位通道 6（TRPC6）的表达上调，与肾小管损伤和炎症相关。db/db 小鼠肾脏和高糖（HG）培养的 HK-2 细胞中 NFATc1 和 TRPC6 的表达也增加，而 TAC 抑制了这些作用。TAC 和 NFATc1 siRNA 可逆转 HK-2 细胞中 HG 诱导的炎症标志物和细胞凋亡，而 TRPC6 质粒则消除了这种作用。此外，HG 诱导的 TRPC6 表达被 NFATc1 siRNA 抑制，而 TAC 抑制 NFATc1 核转位，但在 HG 条件下 HK-2 细胞中的 TRPC6 质粒则恢复了 NFATc1 核转位。这些发现表明，TAC 通过 NFATc1/TRPC6 反馈环改善 DN 中的肾小管间质炎症。
