The effects of anti-angiogenesis agent, malato de sunitinib (Sutent), administration in the 5/6 renal ablation (Nx) model

• Grant number: 11/10943-4
• Support Opportunities: Regular Research Grants
• Duration: September 01, 2011 - August 31, 2013
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Clarice Kazue Fujihara
• Grantee: Clarice Kazue Fujihara
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Denise Maria Avancini Costa Malheiros ; Roberto Zatz

Abstract

The role of new vessel formation in the pathogenesis of chronic kidney disease (CKD) is currently unclear and has fueled a heated controversy. Part of the available evidence suggests that neoangiogenesis exerts a beneficial effect in CKD, acting in the process of reconstruction and reorganization of the damaged tissue. However, other experimental findings indicate that new capillary formation may instead constitute a pathogenic factor, helping to convey blood-borne inflammatory cells to the damaged tissue, thus amplifying and propagating the complex chain of events that culminates with progressive renal fibrosis. VEGF (Vascular Endothelial Growth Factor) is the main stimulus for angiogenesis, promoting endothelial cell proliferation through activation of specific tyrosine kinase receptors, the most important of which is VEGFR2. VEGF inhibitors, acting on VEGF itself or on its receptors, have been utilized in the treatment of some solid tumors, in an attempt at detaining their growth by limiting blood supply. By analogy, it might be expected that these drugs exerted a beneficial effect on CKD, provided that formation of new vessels does indeed participate in the pathogenesis of this process.The aim of the proposed project is to investigate the effect of the inhibitor of the tyrosine kinase action of VEGF receptors 1 and 2, sunitinib (Su) on the progression of renal injury in rats subjected to 5/6 renal ablation (Nx), a widely employed CKD model. Our working hypothesis is that, as a result of its antiangiogenic action, the use of Su will exert a renoprotective effect, slowing the progression of renal injury and, particularly, inflammation and fibrosis of the renal interstitium, which depend strongly on the provision of inflammatory cells brought by the circulation. It is conceivable, however, that this beneficial effect of Su is partially offset by a toxic action on endothelial cells, which has been described in some patients that received the compound for cancer treatment. Some preliminary results suggest that these conflicting effects may indeed occur. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MACHADO, FLAVIA G.; KURIKI, PATRICIA SEMEDO; FUJIHARA, CLARICE K.; FANELLI, CAMILLA; ARIAS, SIMONE C. A.; MALHEIROS, DENISE M. A. C.; CAMARA, NIELS O. S.; ZATZ, ROBERTO. Chronic VEGF Blockade Worsens Glomerular Injury in the Remnant Kidney Model. PLoS One, v. 7, n. 6, JUN 22 2012. (11/10943-4)

OKABE, CRISTIENE; BORGES, RAQUEL LERNER; DE ALMEIDA, DANILO CANDIDO; FANELLI, CAMILLA; BARLETTE, GRASIELA PEDREIRA; MACHADO, FLAVIA GOMES; ALARCON ARIAS, SIMONE COSTA; AVANCINI COSTA MALHEIROS, DENISE MARIA; SARAIVA CAMARA, NIELS OLSEN; ZATZ, ROBERTO; et al. NF-kappa B activation mediates crystal translocation and interstitial inflammation in adenine overload nephropathy. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, v. 305, n. 2, p. F155-F163, JUL 2013. (12/08775-9, 11/10943-4)