Discoidin Domain Receptor 1 Is a Major Mediator of Inflammation and Fibrosis in Obstructive Nephropathy

Abstract

The interactions between tubulointerstitial infiltrating cells and the extracellular matrix play an important role in regulating renal fibrosis. Discoidin domain receptor 1 (DDR1) is a nonintegrin tyrosine kinase receptor for collagen implicated in cell adhesion, proliferation, and extracellular matrix remodeling. We have previously demonstrated that transgenic mice lacking DDR1 are protected from hypertension-associated renal fibrosis. The purpose of this study was to determine the role of DDR1 in renal inflammation and fibrosis related to primitive tubulointerstitial injury. After 12 days of unilateral ureteral obstruction (UUO), kidney histopathologic and real-time quantitative PCR analyses were performed in DDR1 ؊/؊ and wild-type mice. DDR1 expression was strongly increased in the obstructed kidney. Wild-type mice developed important perivascular and interstitial inflammation and fibrosis. In comparison, DDR1 ؊/؊ mice displayed reduced accumulation of fibrillar collagen and transforming growth factor ␤ expression. F4/80 ؉ cell count and proinflammatory cytokines were remarkably blunted in DDR1 ؊/؊ obstructed kidneys. Leukocyte rolling and adhesion evaluated by intravital microscopy were not different between DDR1 ؊/؊ and wild-type mice. Importantly, macrophages isolated from DDR1 ؊/؊ mice presented similar M1/M2 polarization but displayed impaired migration in response to monocyte chemoattractant protein-1. Together, these data suggest that DDR1 plays an important role in the pathogenesis of renal disease via enhanced inflammation. Inhibition of DDR1 expression or activity may represent a novel therapeutic target against the progression of renal diseases. Renal fibrosis is the consequence of the accumulation of extracellular matrix (ECM) components, including collagen, in the kidney. In chronic kidney diseases, irrespective of the initiating cause, fibrotic lesions autoaggravate, leading to a progressive decrease in renal function. Despite growing interest, the pathophysiologic pathways responsible for the progression of renal fibrosis remain elusive. A better understanding of specific mechanisms that promote inflammation and ECM synthesis is of critical importance in this setting because such pathways are susceptible to being at the cornerstone of the initiation and the progression of fibrogenesis.Discoidin domain receptor 1 (DDR1) is a tyrosine kinase transmembrane receptor for collagen constitutively expressed in several cell types and organs, including the gastrointestinal tract, lung, and kidney. 1 In the mammalian kidney, DDR1 is predominantly expressed by vascular smooth muscle cells, mesangial cells, and epithelial cells in normal conditions. 2,3 On activation by binding to collagen I to VI and VIII, DDR1 regulates cell differentiation, adhesion, proliferation, and ECM remodeling. 4 -6 A number of studies have shown that DDR1 is implicated in carcinogenesis, inflammation, atherosclerosis, and fibrogenesis. [7][8][9][10][11][12] Consistent with an important pathogenetic role in vascular diseases, 8,[1...

Genomic and genome-wide association of susceptibility to radiation-induced fibrotic lung disease in mice

“…For example, pulmonary fibrosis can occur as a result of increased extracellular matrix deposition and genes involved in this process such as Abl2 and Ddr1 [42,43] were identified to have variation significantly associated with the trait. Supporting this, Ddr1 -/-mice have been shown to develop a reduced amount of pulmonary fibrosis in response to a related challenge, that of bleomycin-induced lung injury [44], and in separate work [45], to be protected from renal fibrosis. An inflammatory contribution to the tissue response of fibrosis has also been suggested [46] and polymorphisms within particular candidate genes which function to alter the inflammatory response (Slamf6, Btnl1) could thus affect susceptibility to radiation-induced lung disease [41,47,48].…”

Imatinib

“…50 DDRs are potent mediators of inflammation and fibrosis, and DDR1 null mice have reduced collagen accumulation and infiltrating inflammatory cells in both angiotensin II-induced renal injury and the UUO model of fibrosis. 51,52 DDR1 null mice are also protected from lipopolysaccharide-induced shock, confirming its pivotal role as a mediator of inflammation. 51 Imatinib inhibits DDRs in vitro, and this effect probably plays a role in imatinib's attenuation of fibrosis and inflammation observed in murine models of kidney disease.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…Discoidin domain receptor 1 (DDR1), a tyrosine kinase receptor for collagen, is involved in cell proliferation, adhesion and ECM remodeling. Mice lacking DDR1 are protected from experimental renal fibrosis and exhibit dampened intrarenal inflammation (345,346). The latter may be related to impaired chemotactic leukocyte migration that depends on DDR1.…”