TGF-β1 has long been considered as a key mediator in diabetic kidney disease (DKD) but anti-TGF-β1 treatment fails clinically, suggesting a diverse role for TGF-β1 in DKD. In the present study, we examined a novel hypothesis that latent TGF-β1 may be protective in DKD mice overexpressing human latent TGF-β1. Streptozotocin-induced Type 1 diabetes was induced in latent TGF-β1 transgenic (Tg) and wild-type (WT) mice. Surprisingly, compared to WT diabetic mice, mice overexpressing latent TGF-β1 were protected from the development of DKD as demonstrated by lowing microalbuminuria and inhibiting renal fibrosis and inflammation, although blood glucose levels were not altered. Mechanistically, the renal protective effects of latent TGF-β1 on DKD were associated with inactivation of both TGF-β/Smad and nuclear factor-κB (NF-κB) signaling pathways. These protective effects were associated with the prevention of renal Smad7 from the Arkadia-induced ubiquitin proteasomal degradation in the diabetic kidney, suggesting protection of renal Smad7 from Arkadia-mediated degradation may be a key mechanism through which latent TGF-β1 inhibits DKD. This was further confirmed in vitro in mesangial cells that knockdown of Arkadia failed but overexpression of Arkadia reversed the protective effects of latent TGF-β1 on high glucose-treated mesangial cells. Latent TGF-β1 may protect kidneys from TGF-β1/Smad3-mediated renal fibrosis and NF-κB-driven renal inflammation in diabetes through inhibiting Arkadia-mediated Smad7 ubiquitin degradation.

中文翻译：

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潜在的 TGF-β1 通过 Arkadia/Smad7 信号传导预防糖尿病肾病


长期以来，TGF-β1 一直被认为是糖尿病肾病 (DKD) 的关键介质，但抗 TGF-β1 治疗在临床上失败，这表明 TGF-β1 在 DKD 中发挥着多种作用。在本研究中，我们检验了一个新的假设，即潜在的 TGF-β1 可能对过度表达人类潜在 TGF-β1 的 DKD 小鼠具有保护作用。链脲佐菌素诱导的 1 型糖尿病是在潜在的 TGF-β1 转基因 (Tg) 和野生型 (WT) 小鼠中诱导的。令人惊讶的是，与 WT 糖尿病小鼠相比，过度表达潜在 TGF-β1 的小鼠可以免受 DKD 的发展，这通过降低微量白蛋白尿和抑制肾纤维化和炎症来证明，尽管血糖水平没有改变。从机制上讲，潜在 TGF-β1 对 DKD 的肾脏保护作用与 TGF-β/Smad 和核因子-κB (NF-κB) 信号通路的失活有关。这些保护作用与预防糖尿病肾中 Arkadia 诱导的肾 Smad7 泛素蛋白酶体降解有关，表明保护肾 Smad7 免受 Arkadia 介导的降解可能是潜在 TGF-β1 抑制 DKD 的关键机制。这在体外肾小球膜细胞中得到进一步证实，Arkadia 的敲低失败，但 Arkadia 的过度表达逆转了潜在 TGF-β1 对高葡萄糖处理的肾小球膜细胞的保护作用。潜在的 TGF-β1 可以通过抑制 Arkadia 介导的 Smad7 泛素降解来保护肾脏免受 TGF-β1/Smad3 介导的肾纤维化和 NF-κB 驱动的糖尿病肾脏炎症的影响。