Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy.
OBJECTIVE
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
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.
Department of Biochemistry, Zhongshan Medical School, Sun Yat-sen University, Guangzhou, People's Republic of China.
T
T
Zhou
X
X
He
R
R
Cheng
B
B
Zhang
R R
RR
Zhang
Y
Y
Chen
Y
Y
Takahashi
A R
AR
Murray
K
K
Lee
G
G
Gao
J-X
JX
Ma
D000818:Animals; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D058990:Molecular Targeted Therapy; D018384:Oxidative Stress / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D012720:Severity of Illness Index; D015854:Up-Regulation / Q000187:drug effects; D051153:Wnt Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
D051157:Frizzled Receptors; D011480:Protease Inhibitors; D012333:RNA, Messenger; D051153:Wnt Proteins; D051176:beta Catenin