title: Discoidin domain receptor 1 null mice are protected against hypertension-induced renal disease.
abstract: A frequent complication of hypertension is the development of chronic renal failure. This pathology usually is initiated by inflammatory events and is characterized by the abnormal accumulation of collagens within the renal tissue. The purpose of this study was to investigate the role of discoidin domain receptor 1 (DDR1), a nonintegrin collagen receptor that displays tyrosine-kinase activity, in the development of renal fibrosis. To this end, hypertension was induced with angiotensin in mice that were genetically deficient of DDR1 and in wild-type controls. After 4 or 6 wk of angiotensin II administration, wild-type mice developed hypertension that was associated with perivascular inflammation, glomerular sclerosis, and proteinuria. Systolic pressure increase was similar in the DDR1-deficient mice, but the histologic lesions of glomerular fibrosis and inflammation were significantly blunted and proteinuria was markedly prevented. Immunostaining for lymphocytes, macrophages, and collagens I and IV was prominent in the renal cortex of wild-type mice but substantially reduced in DDR1 null mice. In separate experiments, renal cortical slices of DDR1 null mice showed a blunted response of chemokines to LPS that was accompanied by a considerable protection against the LPS-induced mortality. These results indicate the importance of DDR1 in mediating inflammation and fibrosis. Use of DDR1 inhibitors could provide a completely novel therapeutic approach against diseases that have these combined pathologies.
authors.affiliation: INSERM U702, Tenon Hospital, Pierre et Marie Curie University, Paris 75020, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Flamant
authors.forename: Sandrine
authors.initials: S
authors.lastname: Placier
authors.forename: Anita
authors.initials: A
authors.lastname: Rodenas
authors.forename: Cyrile Anne
authors.initials: CA
authors.lastname: Curat
authors.forename: Wolfgang F
authors.initials: WF
authors.lastname: Vogel
authors.forename: Christos
authors.initials: C
authors.lastname: Chatziantoniou
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Dussaule
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D000070818:Discoidin Domain Receptors; D004195:Disease Models, Animal; D005355:Fibrosis; D006973:Hypertension / Q000150:complications*; D007249:Inflammation; D007676:Kidney Failure, Chronic / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D007678:Kidney Glomerulus / Q000473:pathology*; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D011975:Receptors, Mitogen / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics; D014662:Vasoconstrictor Agents / Q000009:adverse effects
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D024042:Collagen Type I; D024141:Collagen Type IV; D016207:Cytokines; D008070:Lipopolysaccharides; D011975:Receptors, Mitogen; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases