AIMS/HYPOTHESIS: The wingless-type MMTV integration site (WNT) pathway mediates multiple physiological and pathological processes, such as inflammation, angiogenesis and fibrosis. The aim of this study was to investigate whether canonical WNT signalling plays a role in the pathogenesis of diabetic nephropathy. METHODS: Expression of WNT ligands and frizzled receptors in the canonical WNT pathway in the kidney was compared at the mRNA level using real-time RT-PCR between Akita mice, streptozotocin-induced diabetic rats and db/db mice and their respective non-diabetic controls. Renal function was evaluated by measuring the urine albumin excretion. Human renal proximal tubular epithelial cells were treated with high-glucose medium and 4-hydroxynonenal (HNE). Levels of β-catenin, connective tissue growth factor and fibronectin were determined by western blot analysis. RESULTS: Some of the WNT ligands and frizzled receptors showed increased mRNA levels in the kidneys of Akita mice, streptozotocin-induced diabetic rats and db/db mice compared with their non-diabetic controls. Renal levels of β-catenin and WNT proteins were upregulated in these diabetic models. Lowering the blood glucose levels by insulin attenuated the activation of WNT signalling in the kidneys of Akita mice. In cultured human renal proximal tubular epithelial cells, both high glucose and HNE activated WNT signalling. Inhibition of WNT signalling with a monoclonal antibody blocking LDL-receptor-related protein 6 ameliorated renal inflammation and fibrosis and reduced proteinuria in Akita mice. CONCLUSIONS/ INTERPRETATION: The WNT pathway is activated in the kidneys of models of both type 1 and 2 diabetes. Dysregulation of the WNT pathway in diabetes represents a new pathogenic mechanism of diabetic nephropathy and renders a new therapeutic target.
AIMS/HYPOTHESIS: The wingless-type MMTV integration site (WNT) pathway mediates multiple physiological and pathological processes, such as inflammation, angiogenesis and fibrosis. The aim of this study was to investigate whether canonical WNT signalling plays a role in the pathogenesis of diabetic nephropathy. METHODS: Expression of WNT ligands and frizzled receptors in the canonical WNT pathway in the kidney was compared at the mRNA level using real-time RT-PCR between Akita mice, streptozotocin-induced diabeticrats and db/db mice and their respective non-diabetic controls. Renal function was evaluated by measuring the urine albumin excretion. Human renal proximal tubular epithelial cells were treated with high-glucose medium and 4-hydroxynonenal (HNE). Levels of β-catenin, connective tissue growth factor and fibronectin were determined by western blot analysis. RESULTS: Some of the WNT ligands and frizzled receptors showed increased mRNA levels in the kidneys of Akita mice, streptozotocin-induced diabeticrats and db/db mice compared with their non-diabetic controls. Renal levels of β-catenin and WNT proteins were upregulated in these diabetic models. Lowering the blood glucose levels by insulin attenuated the activation of WNT signalling in the kidneys of Akita mice. In cultured human renal proximal tubular epithelial cells, both high glucose and HNE activated WNT signalling. Inhibition of WNT signalling with a monoclonal antibody blocking LDL-receptor-related protein 6 ameliorated renal inflammation and fibrosis and reduced proteinuria in Akita mice. CONCLUSIONS/ INTERPRETATION: The WNT pathway is activated in the kidneys of models of both type 1 and 2 diabetes. Dysregulation of the WNT pathway in diabetes represents a new pathogenic mechanism of diabetic nephropathy and renders a new therapeutic target.
Authors: Guadalupe Ortiz-Muñoz; Virginia Lopez-Parra; Oscar Lopez-Franco; Paula Fernandez-Vizarra; Beñat Mallavia; Claudio Flores; Ana Sanz; Julia Blanco; Sergio Mezzano; Alberto Ortiz; Jesus Egido; Carmen Gomez-Guerrero Journal: J Am Soc Nephrol Date: 2010-02-25 Impact factor: 10.121
Authors: Shuei-Liong Lin; Bing Li; Sujata Rao; Eun-Jin Yeo; Thomas E Hudson; Brian T Nowlin; Huaying Pei; Lijun Chen; Jie J Zheng; Thomas J Carroll; Jeffrey W Pollard; Andrew P McMahon; Richard A Lang; Jeremy S Duffield Journal: Proc Natl Acad Sci U S A Date: 2010-02-16 Impact factor: 11.205
Authors: Yashpal S Kanwar; Jun Wada; Lin Sun; Ping Xie; Elisabeth I Wallner; Sheldon Chen; Sumant Chugh; Farhad R Danesh Journal: Exp Biol Med (Maywood) Date: 2008-01
Authors: Ying Chen; Yang Hu; Ti Zhou; Kevin K Zhou; Robert Mott; Mingyuan Wu; Michael Boulton; Timothy J Lyons; Guoquan Gao; Jian-xing Ma Journal: Am J Pathol Date: 2009-11-05 Impact factor: 4.307
Authors: Kelli M Sas; Hong Yin; Wayne R Fitzgibbon; Catalin F Baicu; Michael R Zile; Stacy L Steele; May Amria; Takamitsu Saigusa; Jason Funk; Marlene A Bunni; Gene P Siegal; Brian J Siroky; John J Bissler; P Darwin Bell Journal: Am J Physiol Renal Physiol Date: 2015-04-22
Authors: Yang Hu; Ying Chen; Mingkai Lin; Kyungwon Lee; Robert A Mott; Jian-xing Ma Journal: Invest Ophthalmol Vis Sci Date: 2013-01-07 Impact factor: 4.799