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. H ypertension frequently is complicated by the development of chronic renal failure, a complex pathology that is initiated by inflammatory events that evolve to increased synthesis and accumulation of extracellular matrix (ECM; mainly collagens) within the renal tissue and lead over time to loss of function and ESRD. To date, no efficient treatment that can stop or, even more desirable, reverse the decline of renal function exists. Therefore, the understanding of the systems and/or mechanisms that are involved in the development of renal vascular inflammation and fibrosis will provide valuable information to design specific pharmacologic targets to treat this incurable disease.Important advancements have been made regarding the mechanisms that are involved in the development of chronic renal failure. These studies focused mainly in the systems or agents that promote ECM synthesis and progression of renal disease. We and other investigators, for instance, clearly identified and characterized the signaling pathways that vasoconstrictor peptides are using to activate collagen synthesis (1-4). Less is known about the mechanisms regarding the postsynthesis regulation of ECM, such as matrix anchoring and interactions with the cell membrane.Among the systems that interact with the ECM are the discoidin domain receptors (DDR). They are the first identified receptor tyrosine kinases that bind directly to the ECM (5). DDR1 binds all types of collagens and is widely expressed in a variety of tissues, including vascular smooth m...

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

“…11 This study revealed reduced renal inflammation in the transgenic mice, which suggests indirect consequences of DDR1 activation on the progression of renal fibrosis through enhanced local inflammation. Such a protective effect of DDR1 deletion secondary to its antiinflammatory effect has been also demonstrated in a model of atherosclerosis in mice.…”

“…We have previously shown that DDR1-deficient mice and WT counterparts present no quantitative difference in circulating leukocytes, lymphocytes, monocytes, and neutrophils. 11 Here, we have found that a subset of the interstitial leukocytes recruited after UUO expressed DDR1. Because DDR1-null mice presented reduced inflammation in the obstructed kidney, we next addressed the issue of a proinflammatory role of DDR1 in macrophages via increased migration or differential M1/M2 polarization.…”

“…[7][8][9][10][11][12] Consistent with an important pathogenetic role in vascular diseases, 8,[13][14][15] we have demonstrated that DDR1-deficient mice were protected against renal vascular lesions induced by a long-term infusion of angiotensin II, a model in which hemodynamic alterations and vascular remodeling play a major role. 11 Whether DDR1 may contribute to the initiating mechanisms and the progression of renal fibrosis irrespective of the initial cause remains unclear. Specifically, the implication of DDR1 remains to be established in lesions triggered by tubular injury.…”

“…[1][2][3] However, current evidence does not support a key role for DDR1 in renal development and physiology, in particular because transgenic mice lacking DDR1 present a close to normal renal phenotype in basal conditions. 11,19 In contrast, DDR1 has been established as an important contributor to a broad variety of pathologic processes, especially in cancer and inflammation, by promoting cell migration, invasion, and survival. 9,10,20 -23 In parallel, several in vitro and in vivo studies have shown that DDR1 was involved in crucial mechanisms leading to fibrogenesis.…”

“…29 -32 When compared with the renal localization of DDR1 expression in murine hypertension-induced renal disease and in Col4A3-deficient mice, our present results, consistent with recent observations of DDR1 ϩ macrophages in atherosclerosis, suggest that DDR1 appears to be induced in cell types that are predominantly activated by the specific disease process and involved in the response to the local injury. 11,25,33 Because we identified an important expression of DDR1 on interstitial macrophages, we hypothesized that the absence of DDR1 in macrophages may protect against UUO-induced lesions in DDR1-deficient mice. To gain insight on the role of DDR1 in macrophages, we performed a step-by-step analysis of the critical phases implicated in macrophage recruitment.…”