Delayed blockade of the kinin B1 receptor reduces renal inflammation and fibrosis in obstructive nephropathy

Renal fibrosis is the common histological feature of advanced glomerular and tubulointerstitial disease leading to end-stage renal disease (ESRD). However, specific antifibrotic therapies to slow down the evolution to ESRD are still absent. Because persistent inflammation is a key event in the development of fibrosis, we hypothesized that the proinflammatory kinin B1 receptor (B1R) could be such a new target. Here we show that, in the unilateral ureteral obstruction model of renal fibrosis, the B1R is overexpressed and that delayed treatment with an orally active non-peptide B1R antagonist blocks macrophage infiltration, leading to a reversal of the level of renal fibrosis. in vivo bone marrow transplantation studies as well as in vitro studies on renal cells show that part of this antifibrotic mechanism of B1R blockade involves a direct effect on resident renal cells by inhibiting chemokine CCL2 and CCL7 expression. These findings suggest that blocking the B1R is a promising antifibrotic therapy.-Klein, J., Gonzalez, J., Duchene, J., Esposito, L., Pradere, J. P., Neau, E., Delage, C., Calise, D., Ahluwalia, A., Carayon, P., Pesquero, J. B., Bader, M., Schanstra, J. P., Bascands, J. L. Delayed blockade of the kinin B1 receptor reduces renal inflammation and fibrosis in obstructive nephropathy. FASEB J. 23, 134-142 (2009)INSERMUniversite Toulouse III Paul SabatierSanofi-AventisBasic Science Fellowship of the Barts and the London CharityINSERM, Dept Renal, F-31432 Toulouse, FranceINSERM, Cardiac Remodeling Team 5, F-31432 Toulouse, FranceUniv Toulouse 3, F-31062 Toulouse, FranceBarts & London Med Sch, William Harvey Res Inst, London, EnglandToulouse Univ Hosp, Nephrol & Kidney Transplantat Dept, CHU Rangueil, Toulouse, FranceINSERM, Zootechny Dept Expt Microsurg, Toulouse, FranceSanofi Aventis R&D, Montpellier, FranceUniversidade Federal de São Paulo, Dept Biophys, Escola Paulista Med, São Paulo, BrazilMax Delbruck Ctr Mol Med, Berlin, GermanyUniversidade Federal de São Paulo, Dept Biophys, Escola Paulista Med, São Paulo, BrazilWeb of Scienc

Toll-Like Receptor Signaling and SIGIRR in Renal Fibrosis upon Unilateral Ureteral Obstruction

Innate immune activation via IL-1R or Toll-like receptors (TLR) contibutes to acute kidney injury but its role in tissue remodeling during chronic kidney disease is unclear. SIGIRR is an inhibitor of TLR-induced cytokine and chemokine expression in intrarenal immune cells, therefore, we hypothesized that Sigirr-deficiency would aggravate postobstructive renal fibrosis. The expression of TLRs as well as endogenous TLR agonists increased within six days after UUO in obstructed compared to unobstructed kidneys while SIGIRR itself was downregulated by day 10. However, lack of SIGIRR did not affect the intrarenal mRNA expression of proinflammatory and profibrotic mediators as well as the numbers of intrarenal macrophages and T cells or morphometric markers of tubular atrophy and interstitial fibrosis. Because SIGIRR is known to block TLR/IL-1R signaling at the level of the intracellular adaptor molecule MyD88 UUO experiments were also performed in mice deficient for either MyD88, TLR2 or TLR9. After UUO there was no significant change of tubular interstitial damage and interstitial fibrosis in neither of these mice compared to wildtype counterparts. Additional in-vitro studies with CD90+ renal fibroblasts revealed that TLR agonists induce the expression of IL-6 and MCP-1/CCL2 but not of TGF-β, collagen-1α or smooth muscle actin. Together, postobstructive renal interstitial fibrosis and tubular atrophy develop independent of SIGIRR, TLR2, TLR9, and MyD88. These data argue against a significant role of these molecules in renal fibrosis

A nest in renal fibrosis?

Sakairi and collaborators show that some tubular cells as well as some interstitial myofibroblasts express the intermediate filament protein nestin. These findings evoke questions about the origin and role of these nestin-positive cells in the development of tubulointerstitial fibrosis

Urinary proteome analysis at 5-year followup of patients with nonoperated ureteropelvic junction obstruction suggests ongoing kidney remodeling

<p>Purpose: Severe ureteropelvic junction obstruction is treated surgically. However, for milder cases most clinical teams adopt a watchful waiting approach and only operate in the presence of significant decline of renal function combined with severe hydronephrosis. Little is known about the long-term consequences of ureteropelvic junction obstruction.</p> <p>Materials and Methods: Using capillary electrophoresis coupled with mass spectrometry, we analyzed the urinary proteome of 42 patients with ureteropelvic junction obstruction 5 years postoperatively or 5 years following spontaneous resolution.</p> <p>Results: At 5-year followup urinary proteomes were similar between patients with early surgical correction of ureteropelvic junction obstruction and age matched controls. In contrast, urinary proteomes differed significantly between conservatively followed patients and controls. Analyses of the proteomic differences suggested ongoing renal or ureteral remodeling in the conservatively followed patients that was not visible clinically.</p> Conclusions: Long-term followup studies are warranted in patients with ureteropelvic junction obstruction, especially those followed conservatively, to determine whether the observed changes in the urinary proteomes become clinically relevant at a later stage