Protective effects of genetic inhibition of Discoidin Domain Receptor 1 in experimental renal disease

Abstract

Chronic kidney disease is a progressive incurable pathology affecting millions of people. Intensive investigations aim to identify targets for therapy. We have previously demonstrated that abnormal expression of the Discoidin Domain Receptor 1 (DDR1) is a key factor of renal disease by promoting inflammation and fibrosis. The present study investigates whether blocking the expression of DDR1 after the initiation of renal disease can delay or arrest the progression of this pathology. Severe renal disease was induced by either injecting nephrotoxic serum (NTS) or performing unilateral ureteral obstruction in mice, and the expression of DDR1 was inhibited by administering antisense oligodeoxynucleotides either at 4 or 8 days after NTS (corresponding to early or more established phases of disease, respectively), or at day 2 after ligation. DDR1 antisense administration at day 4 stopped the increase of proteinuria and protected animals against the progression of glomeruloneprhitis, as evidenced by functional, structural and cellular indexes. Antisense administration at day 8 delayed progression –but to a smaller degree- of renal disease. Similar beneficial effects on renal structure and inflammation were observed with the antisense administration of DDR1 after ureteral ligation. Thus, targeting DDR1 can be a promising strategy in the treatment of chronic kidney disease.

The Role of Discoidin Domain Receptor 1 in Inflammation, Fibrosis and Renal Disease

“…When DDR1 was inhibited at the late phase of disease, the macrophage infiltration associated with tumor necrosis factor α and MCP-1 and fibrillar collagen deposits were significantly decreased as well. These results have shown that DDR1 inhibition after the onset of the glomerular disease efficiently protected the animals even if the treatment was administered at a later stage of the pathology [42] . Similar results were obtained with the UUO model: the delayed inhibition of DDR1 preserved the deterioration of renal structure as AS administration blunted tubular dilation, macrophage infiltration and interstitial collagen accumulation showing that DR1 blockade-induced protection was not model-dependent [42] .…”

“…These results have shown that DDR1 inhibition after the onset of the glomerular disease efficiently protected the animals even if the treatment was administered at a later stage of the pathology [42] . Similar results were obtained with the UUO model: the delayed inhibition of DDR1 preserved the deterioration of renal structure as AS administration blunted tubular dilation, macrophage infiltration and interstitial collagen accumulation showing that DR1 blockade-induced protection was not model-dependent [42] . These results provide the proof of concept that DDR1 is an interesting therapeutic target and that its inhibition can stop or reverse the progression of CKD.…”

“…In 2010, Hahn et al [43] pointed out an association between several DDR1 polymorphisms and the progression of IgA nephropathy in children. In addition, we have shown in a limited number of patients' biopsies that DDR1 is expressed in glomeruli in different glomerulopathies, such as lupus nephritis and Goodpasture's syndrome [41,42] . A thorough study about the expression of DDR1 in human kidney disease is yet to be conducted.…”

“…Thus, subsequent experiments were performed to demonstrate whether or not DDR1 blockade can be used efficiently as a therapy approach. To test this, curative protocols were applied in 2 different models of CKD, NTS-induced glomerulonephritis and UUO [42] . WT mice were injected every 48 h either with AS targeting DDR1, non-specific scrambled oligodeoxynucleotides or saline, after the onset of the disease: from day 4 (early phase) or day 8 (intermediate phase), or from day 2 after the ligation, in the NTS or UUO protocols, respectively.…”

“…The surprise future of DDR1 is that in addition to the fibrotic action, it is also strongly involved in the inflammatory process. In the case of renal pathology, it has been demonstrated that DDR1 is induced locally in cell types that are involved in the response to the renal injury: renal vessels and mesangium in hypertension [38] , podocytes in a model of Alport's syndrome [18] and in the NTS-induced glomerulonephritis [41,42] , and tubules and macrophages in the UUO model [40,42] . It was possible to display the major role of DDR1 in the progression of inflammation and fibrosis in these models of CKD by using mice lacking DDR1.…”