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  • The role of DDR in glomerular injury has been


    The role of DDR1 in glomerular injury has been then further studied by the Chatziantoniou group in experimentally-induced crescentic glomerulonephritis, by injection of alloimmune sheep nephrotoxic serum (NTS) [54]. Glomerulonephritis produced a 17-fold increase of DDR1 expression, predominantly in glomeruli and in NTS-treated WT mice, and administration of DDR1-specific ASOs, 48 h before the first injection of the NTS, decreased DDR1 expression and protected renal function and structure compared to control mice receiving scrambled ASOs [54]. This study, provided the first evidence for a therapeutic role of DDR1 in renal glomerulonephritis by decreasing expression of DDR1 via ASOs (though in a prevention regime, rather than full genetic ablation). A second study by the same group further expanded the concept showing that blockade of e expression of DDR1 using ASOs, after the initiation of renal disease, could still protect the kidney [46]. Finally, the group of A. Pozzi at Vanderbilt University provided evidence that DDR1 genetic ablation attenuated glomerulosclerosis and proteinuria in a mouse model of remnant kidney [55]. Nevertheless, the evidence for a role of DDR1 in experimentally-induced renal disease is not uniquely restricted to the glomerular compartment. The Paris-based group of Chatziantoniou and Dussaule explored the role of DDR1 in renal inflammation and fibrosis related to primitive tubule-interstitial injury. The authors were able to show (using unilateral ureteral obstruction (UUO), in conjunction with DDR1−/− and wild-type mice), that genetic DNQX disodium salt of DDR1 reduced accumulation of fibrillar collagen, transforming growth factor (TGF)-β expression, and pro-inflammatory cytokines 12 days after UUO [45]. A later study then showed that administration of ASOs 2 days after ligation resulted in beneficial effects on renal structure and inflammation [46]. Finally, co-authors of the present work (A.S., S.M., M.M. and M.P.) have demonstrated, using a potent and highly selective DDR1 inhibitor (selective against the entire kinome and the closely related DDR2 receptor) developed by Chugai Pharmaceutical Ltd., that DDR1 inhibition improved both renal function and histological parameters in the NTS mouse model of crescentic glomerulonephritis using a prophylactic regime [19]. The protective effect of DDR1 inhibition was further corroborated using a therapeutic intervention regime in a closely related animal model [19]. Together, these data suggest that DDR1 plays a pivotal role in the pathogenesis of renal fibrosis and glomerulosclerosis, a role further corroborated by in vivo results, using a completely independent compound series, recently showed to prevent renal function loss in Alport mice [56].
    Insights from the lung and experimentally-induced lung fibrosis The role of DDR1 in experimentally-induced lung fibrosis relies on three scientific reports [[57], [58], [59]]. The first evidence for a protective role of DDR1 deletion in lung fibrosis was generated in 2006 by the research group of Dr. Vogel in Gottingen, Germany. The authors hypothesized that DDR1 mediated disease progression after lung injury. The hypothesis was based on previous findings showing increased DDR1 expression in bronchoalveolar lavage cells from patients with idiopathic pulmonary fibrosis [36]. This paper [60,61] was later retracted (as were several other works by Wataru Matsuyama [39]) leaving the scientific community with no reliable translational data for DDR1 in lung fibrosis. Still, the authors convincingly demonstrated (using a deletion paradigm) that DDR1-null mice were largely protected against bleomycin(BLM)-induced injury [58]. Further, myofibroblast expansion, apoptosis, and inflammation were reduced in these animals, thus indicating that DDR1 expression is a prerequisite for the development of lung inflammation and fibrosis [58]. Importantly, the above results have been recently confirmed using a pharmacological approach (and therapeutic regimes) by Wang Z. et al. [62]. Mice were treated with compound 6j (a trahydroisoquinoline derivative) after the onset of a BLM challenge. Compound 6j prevented BLM-induced pathological changes (i.e., reduction in alveolar spaces and ECM deposition assessed by Masson\'s trichrome) in a dose-dependent manner. This histological result was accompanied by reduced expression levels of fibrotic markers fibronectin, α-SMA, and collagen (as assessed by hydroxyproline content). These data collectively suggest the promising therapeutic potential of 6j against BLM-induced pulmonary fibrosis. Interestingly, the same group later explored the role of DDR1 in a LPS-induced model of acute lung injury (ALI), a deadly cause of serious lung inflammation [59]; the compound used (referred to as 7ae) exhibited promising in vivo anti-inflammatory effects.