title: The effects of PTK787/ZK222584, an inhibitor of VEGFR and PDGFRβ pathways, on intussusceptive angiogenesis and glomerular recovery from Thy1.1 nephritis.
abstract: The aim of our study was to investigate the phenomenon of intussusceptive angiogenesis with a focus on its molecular regulation by vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor β (PDGFRβ) pathways and biological significance for glomerular recovery after acute injury. Glomerular healing by intussusception was examined in a particular setting of Thy1.1 nephritis, where the lysis of mesangial cells results in an initial collapse and successive rebuilding of glomerular capillary structure. Restoration of capillary structure after induction of Thy1.1 nephritis occurred by intussusceptive angiogenesis resulting in i) rapid expansion of the capillary plexus with reinstatement of the glomerular filtration surface and ii) restoration of the archetypical glomerular vascular pattern. Glomerular capillaries of nephritic rats after combined VEGFR2 and PDGFRβ inhibition by PTK787/ZK222584 (PTK/ZK) were tortuous and irregular. However, the onset of intussusceptive angiogenesis was influenced only after long-term PTK/ZK treatment, providing an important insight into differential molecular regulation between sprouting and intussusceptive angiogenesis. PTK/ZK treatment abolished α-smooth muscle actin and tensin expression by injured mesangial cells, impaired glomerular filtration of microspheres, and led to the reduction of glomerular volume and the presence of multiple hemorrhages detectable in the tubular system. Collectively, treatment of nephritic patients with PTK/ZK compound is not recommended.
authors: Department of Nephrology and Hypertension, Inselspital, University of Bern Medical School, Bern, Switzerland.
authors: Monika
authors: M
authors: Wnuk
authors: Ruslan
authors: R
authors: Hlushchuk
authors: Gérald
authors: G
authors: Tuffin
authors: Uyen
authors: U
authors: Huynh-Do
authors: Valentin
authors: V
authors: Djonov
mesh_terms: D000199:Actins / Q000737:chemistry; D000818:Animals; D005919:Glomerular Filtration Rate; D007668:Kidney / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins / Q000737:chemistry; D018613:Microscopy, Confocal / Q000379:methods; D009389:Neovascularization, Pathologic; D009393:Nephritis / Q000188:drug therapy* / Q000378:metabolism; D010793:Phthalazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D000070876:Tensins; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
chemical_list: D000199:Actins; D008840:Microfilament Proteins; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D000070876:Tensins; C000603372:Tns1 protein, rat; C404768:vatalanib; D020797:Receptor, Platelet-Derived Growth Factor beta; D040281:Vascular Endothelial Growth Factor Receptor-1