title: Smad7 protects against chronic aristolochic acid nephropathy in mice.
abstract: Chronic Aristolochic Acid Nephropathy (AAN) is a progressive chronic kidney disease related to herb medicine. However, treatment for chronic AAN remains ineffective. We report here that Smad7 is protective and has therapeutic potential for chronic AAN. In a mouse model of chronic AAN, progressive renal injury was associated with a loss of renal Smad7 and disruption of Smad7 largely aggravated the severity of chronic AAN as demonstrated by a significant increase in levels of 24-hour urinary protein excretion, serum creatinine, and progressive renal fibrosis and inflammation. In contrast, restored Smad7 locally in the kidneys of Smad7 knockout mice prevented the progression of chronic AAN. Further studies revealed that worsen chronic AAN in Smad7 knockout mice was associated with enhanced activation of TGF-β/Smad3 and NF-κB signaling pathways, which was reversed when renal Smad7 was restored. Importantly, we also found that overexpression of Smad7 locally in the kidneys with established chronic AAN was capable of attenuating progressive chronic AAN by inactivating TGF-β/Smad3-medated renal fibrosis and NF-κB-driven renal inflammation. In conclusion, Smad7 plays a protective role in the pathogenesis of chronic AAN and overexpression of Smad7 may represent a novel therapeutic potential for chronic AAN.
authors.affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.|Division of Nephrology, West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Dai
authors.affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.|Division of Nephrology, West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Xiao-Ru
authors.initials: XR
authors.lastname: Huang
authors.affiliation: Division of Nephrology, West China Hospital of Sichuan University, Chengdu, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Fu
authors.affiliation: Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, and Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Hui-Yao
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000633:toxicity*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000633:toxicity*; D018014:Gene Transfer Techniques; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D051906:Smad7 Protein / Q000378:metabolism*
chemical_list: D034341:Aristolochic Acids; D004365:Drugs, Chinese Herbal; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; C000228:aristolochic acid I
keywords: Pathology Section; Smad7; chronic aristolochic acid nephropathy; renal fibrosis; renal inflammation