Produção Nacional
Revisado por pares
Bradykinin receptor 1 activation exacerbates experimental focal and segmental glomerulosclerosis
2011; Elsevier BV; Volume: 79; Issue: 11 Linguagem: Inglês
10.1038/ki.2011.14
ISSN1523-1755
AutoresRafael Luiz Pereira, Bruna N. Buscariollo, Matheus Corrêa-Costa, Patrícia Semedo, Cassiano Donizetti de Oliveira, Vanessa O. Reis, Edgar Maquigussa, Ronaldo C. Araújo, Tárcio Teodoro Braga, Maria Fernanda Soares, Ivan Cruz Moura, Denise Maria Avancini Costa Malheiros, A. P. Silva Filho, Alexandre C. Keller, Niels Olsen Saraiva Câmara,
Tópico(s)Mast cells and histamine
ResumoFocal and segmental glomerulosclerosis (FSGS) is one of the most important causes of end-stage renal failure. The bradykinin B1 receptor has been associated with tissue inflammation and renal fibrosis. To test for a role of the bradykinin B1 receptor in podocyte injury, we pharmacologically modulated its activity at different time points in an adriamycin-induced mouse model of FSGS. Estimated albuminuria and urinary protein to creatinine ratios correlated with podocytopathy. Adriamycin injection led to loss of body weight, proteinuria, and upregulation of B1 receptor mRNA. Early treatment with a B1 antagonist reduced albuminuria and glomerulosclerosis, and inhibited the adriamycin-induced downregulation of podocin, nephrin, and α-actinin-4 expression. Moreover, delayed treatment with antagonist also induced podocyte protection. Conversely, a B1 agonist aggravated renal dysfunction and even further suppressed the levels of podocyte-related molecules. Thus, we propose that kinin has a crucial role in the pathogenesis of FSGS operating through bradykinin B1 receptor signaling. Focal and segmental glomerulosclerosis (FSGS) is one of the most important causes of end-stage renal failure. The bradykinin B1 receptor has been associated with tissue inflammation and renal fibrosis. To test for a role of the bradykinin B1 receptor in podocyte injury, we pharmacologically modulated its activity at different time points in an adriamycin-induced mouse model of FSGS. Estimated albuminuria and urinary protein to creatinine ratios correlated with podocytopathy. Adriamycin injection led to loss of body weight, proteinuria, and upregulation of B1 receptor mRNA. Early treatment with a B1 antagonist reduced albuminuria and glomerulosclerosis, and inhibited the adriamycin-induced downregulation of podocin, nephrin, and α-actinin-4 expression. Moreover, delayed treatment with antagonist also induced podocyte protection. Conversely, a B1 agonist aggravated renal dysfunction and even further suppressed the levels of podocyte-related molecules. Thus, we propose that kinin has a crucial role in the pathogenesis of FSGS operating through bradykinin B1 receptor signaling. Focal and segmental glomerulosclerosis (FSGS) is one of the most important causes of end-stage renal failure.1.LeBrun C.J. Diehl L.F. Abbott K.C. et al.Life expectancy benefits of cancer screening in the end-stage renal disease population.Am J Kidney Dis. 2000; 35: 237-243Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 2.Seikaly M. Ho P.L. Emmett L. et al.The 12th Annual Report of the North American Pediatric Renal Transplant Cooperative Study: renal transplantation from 1987 through 1998.Pediatr Transplant. 2001; 5: 215-231Crossref PubMed Scopus (180) Google Scholar FSGS is characterized by areas of glomerular sclerosis associated with tubular atrophy and interstitial fibrosis with commitment of the podocytes that lead to proteinuria.3.Franceschini N. Hogan S.L. Falk R.J. Primum non nocere: should adults with idiopathic FSGS receive steroids?.Semin Nephrol. 2003; 23: 229-233Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Podocytes are polarized cells that possess a cytoskeleton that modulates their foot processes that adhere to the glomerular basement membrane.4.Kerjaschki D. Caught flat-footed: podocyte damage and the molecular bases of focal glomerulosclerosis.J Clin Invest. 2001; 108: 1583-1587Crossref PubMed Scopus (266) Google Scholar, 5.Kretzler M. Teixeira V.P. Unschuld P.G. et al.Integrin-linked kinase as a candidate downstream effector in proteinuria.FASEB J. 2001; 15: 1843-1845Crossref PubMed Scopus (95) Google Scholar The foot processes are linked laterally by negative charge structures named slit diaphragms,5.Kretzler M. Teixeira V.P. Unschuld P.G. et al.Integrin-linked kinase as a candidate downstream effector in proteinuria.FASEB J. 2001; 15: 1843-1845Crossref PubMed Scopus (95) Google Scholar that are an important filtration barrier composed of many proteins like nephrin (NPHS-1), NEPH-1, podocin (NPHS-2), CD2AP, ZO-1, and α-actinin-4.4.Kerjaschki D. Caught flat-footed: podocyte damage and the molecular bases of focal glomerulosclerosis.J Clin Invest. 2001; 108: 1583-1587Crossref PubMed Scopus (266) Google Scholar, 6.Donoviel D.B. Freed D.D. Vogel H. et al.Proteinuria and perinatal lethality in mice lacking NEPH1, a novel protein with homology to NEPHRIN.Mol Cell Biol. 2001; 21: 4829-4836Crossref PubMed Scopus (351) Google Scholar, 7.Drenckhahn D. Franke R.P. Ultrastructural organization of contractile and cytoskeletal proteins in glomerular podocytes of chicken, rat, and man.Lab Invest. 1988; 59: 673-682PubMed Google Scholar Recently, some experimental data demonstrated a protective role of bradykinin blockade in acute and chronic kidney injury models.8.Wang P.H. Cenedeze M.A. Campanholle G. et al.Deletion of bradykinin B1 receptor reduces renal fibrosis.Int Immunopharmacol. 2009; 9: 653-657Crossref PubMed Scopus (29) Google Scholar Bradykinin signals through two G-protein-coupled receptors, the B1 (B1RBK) and B2 (B2RBK) receptors. B2RBK is constitutively expressed in most tissues and mediates the majority of the physiological actions of kinins. On the other hand, B1RBK is overexpressed in inflammatory conditions.9.Marin-Castano M.E. Schanstra J.P. Praddaude F. et al.Differential induction of functional B1-bradykinin receptors along the rat nephron in endotoxin induced inflammation.Kidney Int. 1998; 54: 1888-1898Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 10.Schanstra J.P. Marin-Castano M.E. Praddaude F. et al.Bradykinin B(1) receptor-mediated changes in renal hemodynamics during endotoxin-induced inflammation.J Am Soc Nephrol. 2000; 11: 1208-1215PubMed Google Scholar The absence or blockade of B1RBK is generally protective in renal disease models.8.Wang P.H. Cenedeze M.A. Campanholle G. et al.Deletion of bradykinin B1 receptor reduces renal fibrosis.Int Immunopharmacol. 2009; 9: 653-657Crossref PubMed Scopus (29) Google Scholar, 11.Wang P.H. Cenedeze M.A. Pesquero J.B. et al.Influence of bradykinin B1 and B2 receptors in the immune response triggered by renal ischemia-reperfusion injury.Int Immunopharmacol. 2006; 6: 1960-1965Crossref PubMed Scopus (19) Google Scholar, 12.Kakoki M. McGarrah R.W. Kim H.S. et al.Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury.Proc Natl Acad Sci USA. 2007; 104: 7576-7581Crossref PubMed Scopus (105) Google Scholar, 13.Klein J. Gonzalez J. Duchene J. et al.Delayed blockade of the kinin B1 receptor reduces renal inflammation and fibrosis in obstructive nephropathy.FASEB J. 2009; 23: 134-142Crossref PubMed Scopus (55) Google Scholar Nevertheless, the role of B1RBK in FSGS is still unclear. Here, we hypothesize that B1RBK also plays an important role in podocytopathy, which is a hallmark of FSGS. Blocking B1RBK signaling could be a new strategy to halt the progression of FSGS and prevent end-stage renal disease. FSGS was induced in BALB/c mice14.Zheng Z. Pavlidis P. Chua S. et al.An ancestral haplotype defines susceptibility to doxorubicin nephropathy in the laboratory mouse.J Am Soc Nephrol. 2006; 17: 1796-1800Crossref PubMed Scopus (40) Google Scholar, 15.Zheng Z. Schmidt-Ott K.M. Chua S. et al.A Mendelian locus on chromosome 16 determines susceptibility to doxorubicin nephropathy in the mouse.Proc Natl Acad Sci USA. 2005; 102: 2502-2507Crossref PubMed Scopus (83) Google Scholar by a single intravenous injection of adriamycin. The adriamycin-induced nephropathy model is a model of FSGS that mimics many features of human disease. The animals with adriamycin nephropathy lost weight (Supplementary Figure S1A online). Serum creatinine was significantly higher in adriamycin-treated animals at day 28 after injection (Supplementary Figure S1B online). We analyzed the urinary protein/creatinine ratio (Supplementary Figure S1C online), estimated the amount of albuminuria (Supplementary Figure S1D online), and quantified the glomerulosclerosis and tubular degeneration at different time points (Supplementary Figure S1E online). The adriamycin-treated animals showed a progressive and significant augmentation in the amount of proteinuria and albuminuria (Supplementary Figure S1C and D online) up to day 14. These animals also presented a progressive increase in glomerulosclerosis and tubular damage (Supplementary Figure S1E online). Download .doc (.06 MB) Help with doc files Supplementary Figure S1 To study the participation of kinin receptors during adriamycin nephropathy, we first evaluated the expression of B1RBK and B2RBK mRNAs using real-time PCR (Figure 1). Treatment with adriamycin induced the expression of B1RBK at 24 h (Figure 1a), and this expression progressively increased thereafter. The relative expression of B2RBK mRNA increased progressively from day 7 until day 14, when its expression stabilized (Figure 1b). The relative expression of B2RBK mRNA increased progressively from day 7 until day 14 (Figure 1b). As previous studies13.Klein J. Gonzalez J. Duchene J. et al.Delayed blockade of the kinin B1 receptor reduces renal inflammation and fibrosis in obstructive nephropathy.FASEB J. 2009; 23: 134-142Crossref PubMed Scopus (55) Google Scholar, 16.Seguin T. Buleon M. Destrube M. et al.Hemodynamic and renal involvement of B1 and B2 kinin receptors during the acute phase of endotoxin shock in mice.Int Immunopharmacol. 2008; 8: 217-221Crossref PubMed Scopus (21) Google Scholar have shown a possible compensatory relationship between B1RBK and B2RBK, characterized by higher B1RBK expression in B2-knockout mice, we evaluated the ratio of B1RBK to B2RBK that was significantly higher in the adriamycin-treated animals from day 1 to day 10 after injection compared with other days (Figure 1c). First, to address whether B1RBK is involved in the initiation of podocytopathy, animals were treated with des-Arg9-[Leu8]-bradykinin (DALBK) on days 1–3 after adriamycin administration and killed on day 4. DALBK-treated animals were fully protected from albuminuria (Figure 2a) and presented less prominent weight loss (Supplementary Figure S2A online) and proteinuria (Supplementary Figure S2B online). Download .jpg (.05 MB) Help with files Supplementary Figure S2 The DALBK treatment augmented the expression of NPHS-2 mRNA (Figure 2b); however, there was no difference in the renal protein levels of this marker (Figure 2c). Another podocyte marker for slit diaphragm selectivity, NPHS-1, appeared to be restored by DALBK treatment (Supplementary Figure S2C online). On the other hand, the mRNA levels of α-actinin-4 showed no difference (Supplementary Figure S2D online); furthermore, mRNA levels of transforming growth factor-β (TGF-β), plasminogen activator inhibitor-1 (PAI-1), and vimentin were upregulated in FSGS. The DALBK treatment downregulated mRNA levels of PAI-1, vimentin (Supplementary Figure S2E and F online), and mRNA and protein levels of tumor necrosis factor-α (TNF-α; Figure 2d and e). We found no difference in TGF-β levels among the groups (Figure 2f). To investigate the effect of early DALBK treatment on podocyte cell structure, we analyzed the glomerular structure by electron microscopy. We observed that DALBK treatment protected against adriamycin-induced podocyte foot process effacement (Figure 2g). The degrees of glomerulosclerosis and tubular damage showed no differences, although the DALBK-treated groups presented no mesangial hypercellularity observed in the adriamycin group (Supplementary Figure S2G online). Here, we evaluated whether B1RBK blockade could lead to long-term renoprotection. Animals were treated with DALBK on days 1–3 and were followed for up to 28 days. Indeed, animals treated with DALBK showed lower albuminuria (Figure 3a), body weight loss, and proteinuria (Supplementary Figure S3A and B online). Download .jpg (.03 MB) Help with files Supplementary Figure S3 The mRNA levels of NPHS-2, which was downregulated with adriamycin, were restored to basal levels with the DALBK treatment (Figure 3b). NPHS-2 protein (Figure 3c), NPHS-1, and ACTN-4 (Supplementary Figure S3C and D online) presented similar results. The DALBK treatment diminished the adriamycin-induced upregulation of mRNA and renal tissue levels of TGF-β (Figure 3d and e) and PAI-1 and vimentin mRNA (Supplementary Figure S3E and F online). The mRNA expression of TNF-α was reduced with DALBK treatment (Figure 3f), and renal α-smooth muscle actin protein expression was less evident in DALBK-treated animals (Figure 4). Furthermore, there was a redistribution of podocin and podoplanin (Figure 4) in the glomeruli. The DALBK-treated animals showed no glomerulosclerosis and a minimal tubular degeneration. Furthermore, the animals showed no mesangial hypercellularity or tubular atrophy (Supplementary Figure S3G–L online), and low levels of serum urea (Supplementary Figure S4 online). Download .jpg (.05 MB) Help with files Supplementary Figure S4 Next, we evaluated whether B1RBK blockade is able to reverse FSGS. To analyze this question, animals were treated on days 4–6 after adriamycin injection and were killed at day 7. Mice treated with DALBK lost significantly less albuminuria (Figure 5a), and presented a lower body weight loss (Supplementary Figure S5A online), proteinuria (Supplementary Figure S5B online), and serum urea levels (Supplementary Figure S4 online) compared with only adriamycin-treated animals. Postponed treatment with DALBK also restored the protein and mRNA levels of podocin (Figure 5a–c) and mRNA level of nephrin (Supplementary Figure S5C online), but no difference was found in α-actinin-4 (Supplementary Figure S5D online). Download .jpg (.04 MB) Help with files Supplementary Figure S5 The renal tissue active protein and mRNA concentrations of TGF-β (Figure 5d and e), which were upregulated after adriamycin treatment, were significantly reduced in the DALBK-treated group. DALBK treatment also diminished the expression of the PAI-1 and vimentin (Supplementary Figure S5E and F online), and prevented the increase in renal mRNA and serum protein levels of TNF-α (Figure 5f and g). The animals treated with DALBK showed no glomerulosclerosis. This result differs from those animals treated with only adriamycin (Supplementary Figure S5G–K online), which on day 7 had a sclerosis index of 5%. We observed lower degrees of tubular degeneration and mesangial hypercellularity and no tubular atrophy in the DALBK-treated group (Supplementary Figure S5G–K online). We next evaluated whether delayed treatment with DALBK could halt the progression of adriamycin nephropathy by treating animals on days 4–6 after adriamycin injection and followed them until day 28. In contrast to the first delayed treatment, the health of the animals improved with time, and on day 28 they showed no signs of albuminuria (Figure 6a) and showed decreases in proteinuria (Supplementary Figure S6A online) and serum urea (Supplementary Figure S4 online). Download .jpg (.05 MB) Help with files Supplementary Figure S6 Furthermore, the levels of podocyte and fibrotic-related proteins were returned to basal levels with delayed DALBK treatment (Supplementary Figure S6A–E online). Interestingly, renal mRNA and protein levels of NPHS-2 were restored to basal levels in the DALBK-treated group (Figure 6b and c). The same was observed for renal mRNA levels of TGF-β and TNF-α (Figure 6d and e). Renal histology analysis showed no signs of adriamycin nephropathy (Supplementary Figure S6F–L online). We observed that neither early nor delayed treatment of the animals with DALBK induced heme oxygenase-1 mRNA expression; however, this molecule was upregulated in adriamycin-treated mice (Supplementary Figure S7 online). Download .jpg (.04 MB) Help with files Supplementary Figure S7 B1RBK can also be positively regulated using an agonist, des-Arg9-bradykinin (DABK). The early activation of B1RBK accelerated the progression of FSGS (Figure 7 and Supplementary Figure S8 online). DABK-treated animals exhibited augmented albuminuria compared with animals subjected to only adriamycin treatment (Figure 7a). However, total proteinuria and body weight were not significantly different from this latter group (Supplementary Figure S8A and B online). Download .jpg (.03 MB) Help with files Supplementary Figure S8 Despite the clinical signs, DABK administration significantly diminished mRNA and protein expression of NPHS-2 (Figure 7b and c), and no differences were found in the other molecules (Figure 7d–f and Supplementary Figure S8C–E online). Furthermore, the B1RBK agonist significantly augmented vimentin mRNA expression (Supplementary Figure S8F online). Moreover, DABK treatment induced tubular atrophy that was not observed in the other groups (Supplementary Figure S8G and H online). Macrophage infiltration was analyzed by flow cytometry and by quantification of chemokine mRNAs associated with this process 17.Wang Y. Wang Y.P. Tay Y.C. et al.Progressive adriamycin nephropathy in mice: sequence of histologic and immunohistochemical events.Kidney Int. 2000; 58: 1797-1804Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 18.Hattori M. Horita S. Yoshioka T. et al.Mesangial phenotypic changes associated with cellular lesions in primary focal segmental glomerulosclerosis.Am J Kidney Dis. 1997; 5: 632-638Abstract Full Text PDF Scopus (24) Google Scholar, 19.GLee V.W. Wang Y. Qin X. et al.Adriamycin nephropathy in severe combined immunodeficient (SCID) mice.Nephrol Dial Transpl. 2006; 21: 3293-3298Crossref PubMed Scopus (26) Google Scholar (Figure 8). By day 4 after adriamycin injection, B1RBK agonist, DABK, markedly augmented the level of macrophages in the kidney (Figure 8d and g). However, at day 7, the group treated with the antagonist, DALBK, had a diminished level of macrophages within the kidneys induced by adriamycin injection (Figure 8e, f, and h). Furthermore, we observed that adriamycin increased the renal levels of MCP-1 (monocyte chemotactic protein-1), at day 4 (Supplementary Figure S9A online) and levels of MCP-1, MIP-1 (macrophage inflammatory protein 1) and RANTES at day 7 (Supplementary Figure S9B, D, F, and H online) after its injection, whereas DALBK diminished them. Interestingly, DABK enhanced the expression of MCP-1 and MIP-1 (Supplementary Figure S 9A and E online). Download .jpg (.03 MB) Help with files Supplementary Figure S9 Matrix metalloproteinase-9 (MMP-9) is a molecule associated with extracellular matrix degradation and decrease of fibrosis.20.Rerrole J.-P. Hertig A. Nguyen G. et al.Plasminogen activator inhibitor type 1 is a potential target in renal fibrogenesis.Kidney Int. 2000; 58: 1841-1850Abstract Full Text Full Text PDF PubMed Google Scholar Here, we observed that DALBK augmented MMP-9 level (Supplementary Figure S10A and C online); on the other hand, adriamycin induced TIMP-1 (tissue inhibitor of matrix metalloprotease-1) expression, a MMP-9 inhibitor, whereas DALBK diminished it (Supplementary Figure S10B and D online). DABK treatment did not alter the levels of these proteins (Supplementary Figure S10A and B online). Download .jpg (.04 MB) Help with files Supplementary Figure S10 Cell proliferation is closely related to tubular and glomerular injury.21.Geleilete T.J.M. Costa R.S. Dantas M. et al.α-Smooth muscle actin and proliferating cell nuclear antigen expression in focal and segmental glomerulosclerosis: functional and structural parameters of renal disease progression.Bras J Med Biol Res. 2001; 34: 985-991Crossref PubMed Scopus (22) Google Scholar We observed strong nuclear staining for proliferating cell nuclear antigen in the tubular and glomerular area of the kidneys in adriamycin-induced nephropathy (Figure 9). Animals treated with DALBK presented less prominent staining (Figure 9c and f). In contrast, DABK treatment augmented the number of proliferating cell nuclear antigen-positive cells (Figure 9d). We observed that delayed treatment with B1RBK antagonist, DALBK, decreased interleukin-1β expression, compared with adriamycin-induced nephropathy group at day 7. In contrast, on day 4, there was no difference in interleukin-1β level among all groups (Supplementary Figure S11 online). Download .jpg (.04 MB) Help with files Supplementary Figure S11 Because B1RBK is involved in many inflammatory and fibrotic disorders,8.Wang P.H. Cenedeze M.A. Campanholle G. et al.Deletion of bradykinin B1 receptor reduces renal fibrosis.Int Immunopharmacol. 2009; 9: 653-657Crossref PubMed Scopus (29) Google Scholar, 12.Kakoki M. McGarrah R.W. Kim H.S. et al.Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury.Proc Natl Acad Sci USA. 2007; 104: 7576-7581Crossref PubMed Scopus (105) Google Scholar, 13.Klein J. Gonzalez J. Duchene J. et al.Delayed blockade of the kinin B1 receptor reduces renal inflammation and fibrosis in obstructive nephropathy.FASEB J. 2009; 23: 134-142Crossref PubMed Scopus (55) Google Scholar, 17.Wang Y. Wang Y.P. Tay Y.C. et al.Progressive adriamycin nephropathy in mice: sequence of histologic and immunohistochemical events.Kidney Int. 2000; 58: 1797-1804Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 22.Ni A. Yin H. Agata J. et al.Overexpression of kinin B1 receptors induces hypertensive response to des-Arg9-bradykinin and susceptibility to inflammation.J Biol Chem. 2003; 278: 219-225Crossref PubMed Scopus (62) Google Scholar, 23.Westermann D. Lettau O. Sobirey M. et al.Doxorubicin cardiomyopathy-induced inflammation and apoptosis are attenuated by gene deletion of the kinin B1 receptor.Biol Chem. 2008; 389: 713-718Crossref PubMed Scopus (21) Google Scholar, 24.Westermann D. Walther T. Savvatis K. et al.Gene deletion of the kinin receptor B1 attenuates cardiac inflammation and fibrosis during the development of experimental diabetic cardiomyopathy.Diabetes. 2009; 58: 1373-1381Crossref PubMed Scopus (91) Google Scholar, 25.Ahluwalia A. Perretti M. Involvement of bradykinin B1 receptors in the polymorphonuclear leukocyte accumulation induced by IL-1 beta in vivo in the mouse.J Immunol. 1996; 156: 269-274PubMed Google Scholar, 26.Ricupero D.A. Romero J.R. Rishikof D.C. et al.Des-Arg(10)-kallidin engagement of the B1 receptor stimulates type I collagen synthesis via stabilization of connective tissue growth factor mRNA.J Biol Chem. 2000; 275: 12475-12480Crossref PubMed Scopus (47) Google Scholar we hypothesized that its blockade could have a protective role in adriamycin-induced FSGS. Several studies have shown that the blockade and deletion of this receptor are associated with less inflammation and fibrosis,23.Westermann D. Lettau O. Sobirey M. et al.Doxorubicin cardiomyopathy-induced inflammation and apoptosis are attenuated by gene deletion of the kinin B1 receptor.Biol Chem. 2008; 389: 713-718Crossref PubMed Scopus (21) Google Scholar, 24.Westermann D. Walther T. Savvatis K. et al.Gene deletion of the kinin receptor B1 attenuates cardiac inflammation and fibrosis during the development of experimental diabetic cardiomyopathy.Diabetes. 2009; 58: 1373-1381Crossref PubMed Scopus (91) Google Scholar, 27.Ferreira J. Campos M.M. Araujo R. et al.The use of kinin B1 and B2 receptor knockout mice and selective antagonists to characterize the nociceptive responses caused by kinins at the spinal level.Neuropharmacology. 2002; 43: 1188-1197Crossref PubMed Scopus (96) Google Scholar, 28.Lagneux C. Bader M. Pesquero J.B. et al.Detrimental implication of B1 receptors in myocardial ischemia: evidence from pharmacological blockade and gene knockout mice.Int Immunopharmacol. 2002; 2: 815-822Crossref PubMed Scopus (58) Google Scholar but no data were reported in FSGS. The upregulation of B1RBK has previously been associated with glomerular diseases.29.Christopher J. Jaffa A.A. Diabetes modulates the expression of glomerular kinin receptors.Int Immunopharmacol. 2002; 2: 1771-1779Crossref PubMed Scopus (22) Google Scholar To assess the role of B1RBK in FSGS, we observed that this receptor is quickly upregulated during the disease, from days 1 to 28, as observed in other studies,13.Klein J. Gonzalez J. Duchene J. et al.Delayed blockade of the kinin B1 receptor reduces renal inflammation and fibrosis in obstructive nephropathy.FASEB J. 2009; 23: 134-142Crossref PubMed Scopus (55) Google Scholar which in turn helped us to determine a strategy to modulate this receptor. Initially, we evaluate whether the early blockade of B1RBK influence the development of FSGS. Because FSGS is a podocyte-related disease,6.Donoviel D.B. Freed D.D. Vogel H. et al.Proteinuria and perinatal lethality in mice lacking NEPH1, a novel protein with homology to NEPHRIN.Mol Cell Biol. 2001; 21: 4829-4836Crossref PubMed Scopus (351) Google Scholar, 17.Wang Y. Wang Y.P. Tay Y.C. et al.Progressive adriamycin nephropathy in mice: sequence of histologic and immunohistochemical events.Kidney Int. 2000; 58: 1797-1804Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 29.Christopher J. Jaffa A.A. Diabetes modulates the expression of glomerular kinin receptors.Int Immunopharmacol. 2002; 2: 1771-1779Crossref PubMed Scopus (22) Google Scholar, 30.Deegens J.K. Dijkman H.B. Borm G.F. et al.Podocyte foot process effacement as a diagnostic tool in focal segmental glomerulosclerosis.Kidney Int. 2008; 74: 1568-1576Abstract Full Text Full Text PDF PubMed Scopus (115) we analyzed the mRNA and protein expression of podocyte markers, such as nephrin, podocin, and α-actinin-4.31.Saleem M.A. Ni L. Witherden I. et al.Co-localization of nephrin, podocin, and the actin cytoskeleton: evidence for a role in podocyte foot process formation.Am J Pathol. 2002; 161: 1459-1466Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 32.Boute N. Gribouval O. Roselli S. et al.NPHS2, encoding the glomerular proteinpodocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome.Nat Genet. 2000; 24: 349-354Crossref PubMed Scopus (1198) Google Scholar Indeed, animals treated with the antagonist were protected, with decreased levels of proteinuria and podocyte damage. Conversely, when we used an agonist for B1RBK, we observed the opposite result, corroborating the idea that the bradykinin acting through B1RBK is deleterious to FSGS progression, as observed in other fibrotic pathologies.8.Wang P.H. Cenedeze M.A. Campanholle G. et al.Deletion of bradykinin B1 receptor reduces renal fibrosis.Int Immunopharmacol. 2009; 9: 653-657Crossref PubMed Scopus (29) Google Scholar, 10.Schanstra J.P. Marin-Castano M.E. Praddaude F. et al.Bradykinin B(1) receptor-mediated changes in renal hemodynamics during endotoxin-induced inflammation.J Am Soc Nephrol. 2000; 11: 1208-1215PubMed Google Scholar, 11.Wang P.H. Cenedeze M.A. Pesquero J.B. et al.Influence of bradykinin B1 and B2 receptors in the immune response triggered by renal ischemia-reperfusion injury.Int Immunopharmacol. 2006; 6: 1960-1965Crossref PubMed Scopus (19) Google Scholar, 12.Kakoki M. McGarrah R.W. Kim H.S. et al.Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury.Proc Natl Acad Sci USA. 2007; 104: 7576-7581Crossref PubMed Scopus (105) Google Scholar, 13.Klein J. Gonzalez J. Duchene J. et al.Delayed bl
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