NSC228155 br DDR role in kidney Thirty eight
DDR1 role in kidney Thirty-eight papers are reported in PubMed upon the keyword search “DDR1 AND kidney”. Careful examination of those papers shows that only 31 are related to DDR1\'s role in glomerulosclerosis and renal fibrosis, 24 of those being research and the rest review articles. Since the original paper describing the cloning of RTK6 (today\'s DDR1) by Laval et al. , it has been established that DDR1 is highly expressed in the adult kidney (Fig. 2), comparable to the expression level in NSC228155 and placenta . The renal expression was confirmed independently by the group of Vogel et al., though the authors suggest that expression is localized to mesangial cells . The first detailed investigation of DDR1 (and DDR2) expression in normal and remnant rat kidney was performed by Lee et al. . The authors showed DDR1 to be expressed with a basolateral staining pattern within renal cortical and medullary tubules, in connecting and collecting tubules continuous with cortical collecting tubules. DDR1 was also shown to be expressed in smooth muscle cells lining arterioles, but no definite glomerular or interstitial staining was observed . In rats undergoing 5/6 nephrectomy (an experimental procedure potently inducing glomerulosclerosis) DDR1 expression occurs within glomeruli of remnant kidneys. Findings of glomerular expression in the remnant kidney, by Lee et al. , formed the basis for further exploration of DDR1\'s role in experimental glomerular diseases. The characterization of the role of DDR1 within glomeruli was further investigated by Gross et al. , carefully analyzing the DDR1-deficient mouse phenotype over a long period of time. The authors showed that the loss of cell-matrix communication in DDR1-deficient podocytes appears to result (under physiological conditions) in excess synthesis of basement membrane proteins leading to disturbed anchorage of foot processes and disruption of the slit diaphragm, suggesting that the interaction between type IV collagen and DDR1 plays an important role in maintaining the structural integrity of the glomerular basement membrane (GBM) . The group of Chatziantoniou & Dussaule at the Hospital Tenon, in Paris , was the first to experimentally investigate the role of DDR1 in the development of glomerulosclerosis. The groups initial hypothesis was that if DDR1 is involved in the fibrogenic process (acting as a collagen receptor and displaying mitogenic properties), then mice lacking functional DDR1 should be protected against renal fibrosis compared with wild-type controls. The authors indeed showed that the renal vasculature of DDR1 null mice displayed a markedly blunted degree of type I and IV collagen expression during angiotensin II infusion, and unexpectedly almost complete absence of infiltrating cells in the renal vessels and glomeruli of DDR1-deficient mice. Those results translated into improved function, with a marked reduction of microalbuminuria in DDR1-deficient mice indicating DDR1 as an important mediator of glomerular inflammation and sclerosis . While Chatziantoniou & Dussaule pioneered the investigation the role of DDR1 in glomerular injury, Vogel\'s team in Gottingen focused on the detailed characterization of DDR1-deficient mice, showing that deletion of the DDR1 gene is associated with a severe decrease in auditory function and substantial structural alterations in the inner ear . That finding, together with the renal phenotype described by Chatziantoniou & Dussaule , encouraged the research team to hypothesize that DDR1 was an integral part of a larger complex including certain collagens, related collagen receptors, and proteins of the actomyosin machinery acting in concert to maintain the tension of the inner ear and an homeostatic microenvironment at the level of the glomeruli. Based on that evidence, the group decided to assess the role of DDR1 in Col4a3−/− mice (so called Alport mice ) a mouse model phenocopying Alport syndrome, a hereditary rare disease closely resembling chronic kidney disease caused by mutations in type IV collagen [52,53]. The resulting paper, by Gross et al. , compared the survival as well as the renal function and structure of DDR1+/+, DDR1+/− or DDR1−/− crossbred with COL4A3−/− mice. Loss of DDR1 in COL4A3−/− mice prolonged lifespan until death from progressive renal fibrosis in a genotype-dependent manner with DDR1−/−/COL4A3−/− having the longer life span. Similarly, loss of DDR1 delayed uremia, reduced proteinuria and preserved podocyte architecture, and reduced glomerular and tubulointerstitial matrix deposition. The authors also investigated DDR1 using immunogold-localization, showing the protein to be expressed in podocytes. Thus, the work of Gross et al.  confirmed the role of DDR1 in glomerular injury and provided, for the first time, evidence for DDR1 expression in podocytes.