BACKGROUND Transforming growth factor (TGF)-β/Smad3 signaling is highly activated in kidneys of patients with type 2 diabetic nephropathy (T2DN), however, the precise role of Smad3 in the pathogenesis of diabetic nephropathy remains unclear. METHODS Smad3 knockout (KO)-db/db mice were generated by intercrossing of male and female double-heterozygous Smad3+/- db/m mice. Renal functions including urinary albumin excretion and serum creatinine were determined. Renal histological injury including renal fibrosis and inflammation were examined by periodic acid Schiff (PAS), periodic acid-silver methenamine (PASM), and immunohistochemistry (IHC) staining. RESULTS Smad3 knockout (KO)-db/db mice were protected from the development of diabetic kidney injury, characterized by the normal levels of urinary albumin excretion and serum creatinine without any evidence for renal fibrosis and inflammation. In contrast, Smad3 wild-type (WT) db/db and Smad3+/- db/db mice developed progressively decline in renal function over the 12 to 32-week time course, including increased microalbuminuria and elevated levels of serum creatinine. Pathologically, Smad3 WT db/db and Smad3+/- db/db mice exhibited a marked deposition of collagen-I (colI), collagen-IV(col-IV), and an increased infiltration of F4/80+ macrophages in kidney. Mechanistically, Smad3 deficiency decreased the lncRNA Erbb4-IR transcription, while increased miR-29b transcription and therefore protected the kidney from progressive renal injury in db/db mice. CONCLUSION Results from this study imply that Smad3 may represent as a novel and effective therapeutic target for T2DN.

中文翻译：

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删除Smad3可防止2型糖尿病肾病的肾纤维化和炎症。

背景技术转化生长因子（TGF）-β/ Smad3信号在2型糖尿病肾病（T2DN）患者的肾脏中被高度激活，但是，尚不清楚Smad3在糖尿病肾病发病机理中的确切作用。方法通过雄性和雌性双杂合Smad3 +/- db / m小鼠的杂交产生Smad3基因敲除（KO）-db / db小鼠。确定肾功能，包括尿白蛋白排泄和血清肌酐。肾脏组织学损伤包括肾纤维化和炎症通过高碘酸席夫（PAS），高碘酸-银二甲胺（PASM）和免疫组化（IHC）染色进行了检查。结果保护了Smad3基因敲除（KO）-db / db小鼠免于糖尿病肾损伤的发展，其特征是尿白蛋白排泄和血清肌酐水平正常，没有任何肾纤维化和炎症的证据。相反，Smad3野生型（WT）db / db和Smad3 +/- db / db小鼠在12至32周的时间过程中肾功能逐渐下降，包括微量白蛋白尿增加和血清肌酐水平升高。病理上，Smad3 WT db / db和Smad3 +/- db / db小鼠表现出胶原蛋白I（colI），胶原蛋白IV（col-IV）的显着沉积以及F4 / 80 +巨噬细胞在肾脏中的浸润增加。从机制上讲，Smad3缺乏症降低了lncRNA Erbb4-IR转录，同时增加了miR-29b转录，因此保护了db / db小鼠肾脏免受进行性肾损伤。