title: The cyclic GMP-dependent protein kinase Iα suppresses kidney fibrosis.
abstract: Cyclic guanosine monophosphate (cGMP) is synthesized by nitric oxide or natriuretic peptide-stimulated guanylyl cyclases and exhibits pleiotropic regulatory functions in the kidney. Hence, integration of cGMP signaling by cGMP-dependent protein kinases (cGKs) might play a critical role in renal physiology; however, detailed renal localization of cGKs is still lacking. Here, we performed an immunohistochemical analysis of cGKIα and cGKIβ isozymes in the mouse kidney and found both in arterioles, the mesangium, and within the cortical interstitium. In contrast to cGKIα, the β-isoform was not detected in the juxtaglomerular apparatus or medullary fibroblasts. Since interstitial fibroblasts play a prominent role in interstitial fibrosis, we focused our study on cGKI function in the interstitium, emphasizing a functional differentiation of both isoforms, and determined whether cGKIs influence renal fibrosis induced by unilateral ureter obstruction. Treatment with the guanylyl cyclase activators YC1 or isosorbide dinitrate showed stronger antifibrotic effects in wild-type than in cGKI-knockout or in smooth muscle-cGKIα-rescue mice, which are cGKI deficient in the kidney except in the renal vasculature. Moreover, fibrosis influenced the mRNA and protein expression levels of cGKIα more strongly than cGKIβ. Thus, our results indicate that cGMP, acting primarily through cGKIα, is an important suppressor of kidney fibrosis.
authors.affiliation: Lehrstuhl für Pharmakologie und Toxikologie, Institut für Pharmazie, Universität Regensburg, Regensburg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schinner
authors.forename: Andrea
authors.initials: A
authors.lastname: Schramm
authors.forename: Frieder
authors.initials: F
authors.lastname: Kees
authors.forename: Franz
authors.initials: F
authors.lastname: Hofmann
authors.forename: Jens
authors.initials: J
authors.lastname: Schlossmann
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D015971:Gene Expression Regulation, Enzymologic; D006162:Guanylate Cyclase / Q000378:metabolism; D007527:Isoenzymes; D007668:Kidney / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D007674:Kidney Diseases / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D057507:Mice, 129 Strain; D012333:RNA, Messenger / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D020536:Enzyme Activators; D005353:Fibronectins; D007527:Isoenzymes; D012333:RNA, Messenger; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D016212:Transforming Growth Factor beta; D054460:rho-Associated Kinases; D062965:Cyclic GMP-Dependent Protein Kinase Type I; C569720:Prkg1 protein, mouse; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D006162:Guanylate Cyclase