Diabetes-induced upregulation of urotensin II and its receptor plays an important role in TGF-beta1-mediated renal fibrosis and dysfunction.
Urotensin II (UII) was identified as the ligand for a novel G protein-coupled receptor, GPR14. UII was found not only to have a potent vasoconstrictive action but also to have profibrotic effects in the heart. The present study was to define whether UII and GPR14 also play important roles in diabetes-induced renal fibrosis and dysfunction. Diabetic rats were induced using streptozotocin, and the rat proximal tubular epithelial cells (NRK-52E) were used for the in vitro mechanism study. Results showed that expression of UII and GPR14 was significantly upregulated at both mRNA and protein levels in the diabetic kidneys compared with controls. The upregulated expressions of UII and GPR14 in the kidney were accompanied by significant increases in the renal profibrotic factor transforming growth factor (TGF)-beta1 expression, the renal extracellular matrix (fibronectin and collagen IV) accumulation, and the renal dysfunction (increases in urinal N-acetyl-beta-d-glucosaminidase content, 24-h urinary retinol-binding protein excretion rate, and decrease in creatinine clearance rate). Exposure of NRK-52E cells to 10(-8) mol/l UII for 48 h caused a significant increase of TGF-beta1, but not ANG II, production that was GPR14- and calcium-dependent, since GPR14 small-interfering RNA and calcium channel blocker nimodipine or calcium chelator EDTA all could abolish the induction of TGF- beta1 by UII. Furthermore, exposure of NRK-52E cells to TGF-beta1 or ANG II also increased UII and GPR14 mRNA expressions. These results suggested that diabetes-induced upregulation of UII and GPR14, most likely through autocrine and/or paracrine mechanisms, plays an important role in TGF-beta1-mediated renal fibrosis and dysfunction.
Tian
Lin
L
Department of Experimental Pharmacology and Toxicology, School of Pharmacy, Jilin University, Changchun, P.R.China.
Li
Cai
C
Qi
Jiping
J
Fu
Peng
P
Yu
Xiaoyan
X
Li
Xiaokun
X
Cai
Lu
L
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002460:Cell Line; D024141:Collagen Type IV / Q000378:metabolism; D003404:Creatinine / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000503:physiopathology / Q000652:urine; D003928:Diabetic Nephropathies / Q000097:blood / Q000503:physiopathology* / Q000652:urine; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D006023:Glycoproteins / Q000378:metabolism; D006596:Hexosaminidases / Q000652:urine; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012177:Retinol-Binding Proteins / Q000652:urine; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014579:Urotensins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000093422:Glycated Serum Proteins
D001786:Blood Glucose; D001798:Blood Proteins; D002121:Calcium Channel Blockers; D024141:Collagen Type IV; D005353:Fibronectins; D006023:Glycoproteins; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D012177:Retinol-Binding Proteins; D053773:Transforming Growth Factor beta1; D014579:Urotensins; C473142:Uts2r protein, rat; C029677:urotensin II; D003404:Creatinine; D006596:Hexosaminidases; D000093422:Glycated Serum Proteins