The role of discoidin domain receptor 2 in the renal dysfunction of alport syndrome mouse model

Abstract

Alport syndrome (AS) is a hereditary glomerular nephritis caused by mutation in one of the type IV collagen genes α3/α4/α5 that encode the heterotrimer COL4A3/4/5. Failure to form a heterotrimer due to mutation leads to the dysfunction of the glomerular basement membrane, and end-stage renal disease. Previous reports have suggested the involvement of the receptor tyrosine kinase discoidin domain receptor (DDR) 1 in the progression of AS pathology. However, due to the similarity between DDR1 and DDR2, the role of DDR2 in AS pathology is unclear. Here, we investigated the involvement of DDR2 in AS using the X-linked AS mouse model. Mice were treated subcutaneously with saline or antisense oligonucleotide (ASO; 5 mg/kg or 15 mg/kg per week) for 8 weeks. Renal function parameters and renal histology were analyzed, and the gene expressions of inflammatory cytokines were determined in renal tissues. The expression level of DDR2 was highly elevated in kidney tissues of AS mice. Knockdown of Ddr2 using Ddr2 -specific ASO decreased the Ddr2 expression. However, the DDR2 ASO treatment did not improve the proteinuria or decrease the BUN level. DDR2 ASO also did not significantly ameliorate the renal injury, inflammation and fibrosis in AS mice. These results showed that Ddr2 knockdown by ASO had no notable effect on the progression of AS indicating that DDR2 may not be critically involved in AS pathology. This finding may provide useful information and further understanding of the role of DDRs in AS.

Genetic and pharmacological tools to study the role of discoidin domain receptors in kidney disease

“…In the UUO model, downregulation of DDR1 expression with AON 2 days after injury reduced inflammation and preserved renal structure ( Kerroch et al, 2016 ). In contrast to this finding, downregulation of DDR2 expression with AON in a mouse model of Alport syndrome did not decrease proteinuria, inflammation or fibrosis ( Sannomiya et al, 2021 ), despite lowering the levels of MCP-1 and collagen I. It is not clear whether lack of overall beneficial effects are due to incomplete depletion of DDR2 or whether DDR2 does not play a role in the kidney injury in this animal model.…”

“…In contrast to DDR1, whether and where DDR2 expression is upregulated in subjects with kidney disease has not been investigated. In some animal models of kidney injury like Alport syndrome ( Sannomiya et al, 2021 ) and UUO ( Li et al, 2019b ), upregulation of DDR2 expression has been shown by Western blot and RT-PCR, respectively. However, no changes in DDR2 expression are observed in the remnant kidney model ( Lee et al, 2004 ).…”

“…To this end, mice lacking DDR2 show reduced renal interstitial fibrosis in the UUO model compared to injured wild-type mice ( Li et al, 2019b ) ( Table 1 ). On the other hand, in vivo downregulation of DDR2 in Alport mice using DDR2-specific antisense oligonucleotide therapy did not improve proteinuria, nor it ameliorated renal injury, inflammation and fibrosis ( Sannomiya et al, 2021 ) ( Table 2 ). Thus, unlike DDR1 ( Gross et al, 2010 ), DDR2 might not be critically involved in the pathogenesis of Alport syndrome.…”

The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer

“…Aside from the main role of DDR1 and DDR2 in human cancer, they are also involved in other disorders such as inflammation, tissue fibrosis and atherosclerosis, and neurodegenerative diseases [ 5 , 90 , 91 , 92 ]. A study by Matsuyama et al, reported that DDR1 not only stimulated inflammatory factor secretion, but it also enhanced the effects of other stimuli including proinflammatory cytokines or bacterial products [ 93 ].…”

Molecular Basis, Diagnostic Challenges and Therapeutic Approaches of Alport Syndrome: A Primer for Clinicians

“…The role of DDR2 (discoidin domain receptor 2), highly similar to DDR1, was investigated in an X-linked AS mouse (B6). DDR2, despite having high expression levels in AS, does not have a clear implication in the pathogenesis of AS [ 69 ].…”