Bi-Hua Xu1, Jingyi Sheng2, Yong-Ke You2, Xiao-Ru Huang2, Ronald C W Ma2, Qingwen Wang3, Hui-Yao Lan4. 1. Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen, China; Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, Lui Chi Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, China. 2. Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen, China. 3. Department of Medicine & Therapeutics, Li Ka Shing Institute of Health Sciences, Lui Chi Woo Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, China.. Electronic address: wqw_sw@163.com. 4. Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen, China. Electronic address: hylan@cuhk.edu.hk.
Abstract
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.
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 acidSchiff (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, Smad3deficiency 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.
Authors: Li Dong; Jian-Chun Li; Zhong-Jing Hu; Xiao-Ru Huang; Li Wang; Hong-Lian Wang; Ronald C W Ma; Hui-Yao Lan; Si-Jin Yang Journal: J Cell Mol Med Date: 2021-03-17 Impact factor: 5.310