title: Chronic VEGF blockade worsens glomerular injury in the remnant kidney model.
abstract: VEGF inhibition can promote renal vascular and parenchymal injury, causing proteinuria, hypertension and thrombotic microangiopathy. The mechanisms underlying these side effects are unclear. We investigated the renal effects of the administration, during 45 days, of sunitinib (Su), a VEGF receptor inhibitor, to rats with 5/6 renal ablation (Nx). Adult male Munich-Wistar rats were distributed among groups S+V, sham-operated rats receiving vehicle only; S+Su, S rats given Su, 4 mg/kg/day; Nx+V, Nx rats receiving V; and Nx+Su, Nx rats receiving Su. Su caused no change in Group S. Seven and 45 days after renal ablation, renal cortical interstitium was expanded, in association with rarefaction of peritubular capillaries. Su did not worsen hypertension, proteinuria or interstitial expansion, nor did it affect capillary rarefaction, suggesting little angiogenic activity in this model. Nx animals exhibited glomerulosclerosis (GS), which was aggravated by Su. This effect could not be explained by podocyte damage, nor could it be ascribed to tuft hypertrophy or hyperplasia. GS may have derived from organization of capillary microthrombi, frequently observed in Group Nx+Su. Treatment with Su did not reduce the fractional glomerular endothelial area, suggesting functional rather than structural cell injury. Chronic VEGF inhibition has little effect on normal rats, but can affect glomerular endothelium when renal damage is already present.
authors: Laboratory of Renal Pathophysiology (LIM-16), Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.
authors: Flavia G
authors: FG
authors: Machado
authors: Patrícia Semedo
authors: PS
authors: Kuriki
authors: Clarice K
authors: CK
authors: Fujihara
authors: Camilla
authors: C
authors: Fanelli
authors: Simone C A
authors: SC
authors: Arias
authors: Denise M A C
authors: DM
authors: Malheiros
authors: Niels O S
authors: NO
authors: Camara
authors: Roberto
authors: R
authors: Zatz
mesh_terms: D000818:Animals; D017115:Catheter Ablation; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced; D007211:Indoles / Q000494:pharmacology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000601:surgery; D007678:Kidney Glomerulus / Q000187:drug effects; D008297:Male; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000077210:Sunitinib