Kinin B1 receptor antagonism is equally efficient as angiotensin receptor 1 antagonism in reducing renal fibrosis in experimental obstructive nephropathy, but is not additive

Abstract

Background: Renal tubulointerstitial fibrosis is the pathological hallmark of chronic kidney disease (CKD). Currently, inhibitors of the renin–angiotensin system (RAS) remain the sole therapy in human displaying antifibrotic properties. Further antifibrotic molecules are needed. We have recently reported that the delayed blockade of the bradykinin B1 receptor (B1R) reduced the development of fibrosis in two animal models of renal fibrosis. The usefulness of new drugs also resides in outperforming the gold standards and eventually being additive or complementary to existing therapies.Methods: In this study we compared the efficacy of a B1R antagonist (B1Ra) with that of an angiotensin type 1 receptor antagonist (AT1a) in the unilateral ureteral obstruction (UUO) model of renal fibrosis and determined whether bi-therapy presented higher efficacy than any of the drugs alone.Results: B1R antagonism was as efficient as the gold-standard AT1a treatment. However, bitherapy did not improve the antifibrotic effects at the protein level. We sought for the reason of the absence of this additive effect by studying the expression of a panel of genes involved in the fibrotic process. Interestingly, at the molecular level the different drugs targeted different players of fibrosis that, however, in this severe model did not result in improved reduction of fibrosis at the protein level.Conclusions: As the B1R is induced specifically in the diseased organ and thus potentially displays low side effects it might be an interesting alternative in cases of poor tolerability to RAS inhibitors.

Differential Expression of Kinin Receptors in Human Wet and Dry Age-Related Macular Degeneration Retinae

“…In human embryonic lung fibroblasts, B1R activation induced collagen I synthesis and fibrogenesis [62]. B1R blockade reversed inflammation and the expression of fibrosis markers (collagen and α-SMA) in renal fibrosis [23,33]. Here, we show a colocalization of B1R with the fibrosis markers (collagen 1α and α-SMA), suggesting a possible implication of B1R in fibrosis formation in human wet AMD.…”

“…Since fibrotic lesions was shown in neovascular AMD [32], and fibrosis was associated with an upregulation of B1R [33], we evaluated the occurrence of fibrosis in both forms of AMD using the expression of α-SMA and collagen 1α as markers [34,35]. Neither the control (Figure 7C,D) nor the dry AMD (Figure 7G,H) retinae showed any specific staining to evidence fibrosis formation.…”

Bradykinin 1 receptor blockade subdues systemic autoimmunity, renal inflammation, and blood pressure in murine lupus nephritis

“…It has been documented that B1R staining was positive in renal tissue of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and Henoch–Schönlein purpura nephritis [5]. B1R blockade or ablation was also documented to be effective in ameliorating renal fibrosis in experimental obstructive nephropathy [7], reducing the renal inflammatory response in cisplatin or LPS-induced acute renal injury and ischemic-reperfusion injury in murine models [6, 23, 24]. In our previous work in anti-GBM–induced experimental nephritis mice, blockade of the B2R bradykinin receptor worsened disease whereas blockade of B1R ameliorated disease [15], once again suggesting the pro-inflammatory and pathogenic role of the B1R in immune-mediated nephritis.…”

“…Indeed, this receptor-mediated pathway has been implicated in inflammatory bowel disease, vasculitis, experimentally induced nephritis, and acute gout [1–4]. In resonance with these reports, it has been shown that B1R antagonism or ablation plays a protective role in nephrotoxic serum-induced glomerulonephritis [5], lipopolysaccharide (LPS)-mediated acute renal inflammation [6], and experimental obstructive nephropathy [7]. However, the renal expression of B1R and its exact role in the pathogenesis of LN are poorly investigated.…”

Kidney tubules

“…Bradykinin’s actions are prolonged by the use of ACE inhibitors, with potentiation of renal bradykinin a potential advantageous therapeutic effect of the ACE inhibitors, in addition to a cause of angioedema [68]. Both kinin receptor inhibition and kinin B 1 and B 2 receptor knockout mice are protected against cisplatin-induced AKI [69▪,70▪], with B 1 receptor antagonists also reducing fibrosis after experimental UUO, presumably because of inhibition of bradykinin’s proinflammatory actions including promotion of migration of immune cells to injured tissue [71]. …”