title: Increasing cGMP-dependent protein kinase activity attenuates unilateral ureteral obstruction-induced renal fibrosis.
abstract: Our previous studies support the protective effect of cGMP and cGMP-dependent protein kinase I (PKG-I) pathway on the development of renal fibrosis. Therefore, in the present studies, we determined whether pharmacologically or genetically increased PKG activity attenuates renal fibrosis in a unilateral ureteral obstruction (UUO) model and also examined the mechanisms involved. To increase PKG activity, we used the phosphodiesterase 5 inhibitor sildenafil and PKG transgenic mice. UUO model was induced in wild-type or PKG-I transgenic mice by ligating the left lateral ureteral and the renal fibrosis was observed after 14 days of ligation. Sildenafil was administered into wild-type UUO mice for 14 days. In vitro, macrophage and proximal tubular cell function was also analyzed. We found that sildenafil treatment or PKG transgenic mice had significantly reduced UUO-induced renal fibrosis, which was associated with reduced TGF-β signaling and reduced macrophage infiltration into kidney interstitial. In vitro data further demonstrated that both macrophages and proximal tubular cells were important sources of UUO-induced renal TGF-β levels. The interaction between macrophages and tubular cells contributes to TGF-β-induced renal fibrosis. Taken together, these data suggest that increasing PKG activity ameliorates renal fibrosis in part through regulation of macrophage and tubular cell function, leading to reduced TGF-β-induced fibrosis.
authors.affiliation: Graduate Center for Nutritional Sciences, Univ. of Kentucky, Wethington Bldg., Rm. 583, 900 S. Limestone St., Lexington, KY 40536. swang7@uky.edu.
authors.forename: Wenpeng
authors.initials: W
authors.lastname: Cui
authors.forename: Hasiyeti
authors.initials: H
authors.lastname: Maimaitiyiming
authors.forename: Xinyu
authors.initials: X
authors.lastname: Qi
authors.forename: Heather
authors.initials: H
authors.lastname: Norman
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhou
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Fu
authors.forename: Shuxia
authors.initials: S
authors.lastname: Wang
mesh_terms: D000199:Actins / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000378:metabolism; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D018836:Inflammation Mediators / Q000378:metabolism; D007674:Kidney Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate; D051899:Smad2 Protein / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation; D014517:Ureteral Obstruction / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology
chemical_list: D000199:Actins; D015820:Cadherins; D017077:Culture Media, Conditioned; D016207:Cytokines; D018836:Inflammation Mediators; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D013450:Sulfones; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C544013:alpha-smooth muscle actin, mouse; D000804:Angiotensin II; D000068677:Sildenafil Citrate; D062965:Cyclic GMP-Dependent Protein Kinase Type I; C569720:Prkg1 protein, mouse
keywords: PKG; TGF-β1; UUO; renal fibrosis