Inducible nitric oxide synthase-derived nitric oxide promotes glomerular angiogenesis via upregulation of vascular endothelial growth factor receptors.
The vascular endothelial growth factor (VEGF) system is of major importance for glomerular endothelial repair in glomerulonephritis (GN) and is significantly affected by nitric oxide (NO) release. For investigating whether glomerular upregulation of inducible NO synthase (iNOS) in GN might affect VEGF-mediated repair, a selective iNOS inhibitor, L-N6-(1-iminoethyl)-lysin (L-NIL), was administered to rats with anti-Thy 1.1 GN from day -2 until day 5 after GN induction. Compared with untreated nephritic rats, L-NIL-treated nephritic rats showed similar mean arterial BP, significantly decreased de novo peak nitrate production, and increased albuminuria on day 6. This was preceded by a significant decrease of glomerular endothelial cell proliferation and endothelial area on day 2 in L-NIL-treated nephritic rats. Upregulation of glomerular VEGF mRNA and protein expression, in particular of the VEGF(164) splicing variant, occurred similarly in L-NIL-treated and untreated nephritic rats on days 2 and 7. However, the upregulation of glomerular VEGF receptor 1 and 2 mRNA expression on day 2 was reduced by 77 and 67%, respectively, in L-NIL-treated nephritic rats as compared with untreated nephritic rats. In parallel, glomerular VEGF(165) binding was reduced by 34% in L-NIL-treated nephritic rats on day 2. Glomerular upregulation of the VEGF(164) co-receptor neuropilin-1 mRNA in nephritic rats was reduced by L-NIL treatment only on day 7. Healthy untreated or L-NIL-treated controls showed no significant differences in any parameter analyzed. In conclusion, impaired repair of glomerular endothelium and downregulation of glomerular VEGF receptor expression was observed after selective iNOS inhibition in experimental GN. These data identify iNOS-derived NO production as the first in vivo regulator of the glomerular VEGF system and as an important mechanism promoting glomerular healing.
Ostendorf
Tammo
T
Division of Nephrology and Immunology, University Hospital Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany. tostendorf@ukaachen.de
Van Roeyen
Claudia
C
Westenfeld
Ralf
R
Gawlik
Alexander
A
Kitahara
Masashi
M
De Heer
Emile
E
Kerjaschki
Dontscho
D
Floege
Jürgen
J
Ketteler
Markus
M
D000818:Animals; D007678:Kidney Glomerulus / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D040262:Receptors, Vascular Endothelial Growth Factor