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...
Increased renal expression of periostin, a protein normally involved in embryonic and dental development, correlates with the decline of renal function in experimental models and patient biopsies. Because periostin has been reported to induce cell differentiation, we investigated whether it is also involved in the development of renal disease and whether blocking its abnormal expression improves renal function and/ or structure. After unilateral ureteral obstruction in wild-type mice, we observed a progressive increase in the expression and synthesis of periostin in the obstructed kidney that associated with the progression of renal lesions. In contrast, mice lacking the periostin gene showed less injury-induced interstitial fibrosis and inflammation and were protected against structural alterations. This protection was associated with a preservation of the renal epithelial phenotype. In vitro, administration of TGF-b to renal epithelial cells increased the expression of periostin several-fold, leading to subsequent loss of the epithelial phenotype. Furthermore, treatment of these cells with periostin increased the expression of collagen I and stimulated the phosphorylation of FAK, p38, and ERK 42/44. In vivo delivery of antisense oligonucleotides to inhibit periostin expression protected animals from L-NAME-induced renal injury. These data strongly suggest that periostin mediates renal disease in response to TGF-b and that blocking periostin may be a promising therapeutic strategy against the development of CKD.
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