Endothelial von Willebrand factor release due to eNOS deficiency predisposes to thrombotic microangiopathy in mouse aging kidney.
Endothelial dysfunction is critical in the decline of renal function with. By using endothelial nitric oxide synthase knockout (eNOSKO) mice, we tested the hypothesis that a lack of endothelial nitric oxide synthase accelerates renal injury in the aging kidney. In contrast to control mice and young eNOSKO mice, aging eNOSKO mice showed greater renal injury and in particular developed a thrombotic microangiopathy, with mesangiolysis, endothelial swelling, endothelial cell loss, double-contour appearance of glomerular basement membrane (GBM), and thrombus formation. Thrombi, which were composed of fibrin, platelets, and von Willebrand factor (vWF), were identified predominantly in glomerular capillaries and rarely in arterioles, but not in larger vessels. In the tubulointerstitium, tubular degeneration and macrophage infiltration were also prominent in aging eNOSKO mice. Intraluminal vWF deposition was accompanied with thrombus formation, whereas mesangial deposition of vWF was associated with mesangial matrix expansion. Furthermore, the mesangial vWF deposition was detectable in young eNOSKO mice in which severe glomerular injury had not yet developed. Finally, a higher level of serum P-selectin in eNOSKO mice was consistent with the vWF behavior and suggested exocytosis of the Weibel-Palade body by the endothelium. In conclusion, a lack of endothelial nitric oxide synthase resulted in the development of glomerular thrombotic microangiopathy. A lack of nitric oxide likely contributed to the release of vWF, leading to thrombus formation in this model.
Nakayama
Takahiro
T
Division of Nephrology, University of Florida, Gainesville, Florida, USA.
Sato
Waichi
W
Yoshimura
Ashio
A
Zhang
Li
L
Kosugi
Tomoki
T
Campbell-Thompson
Martha
M
Kojima
Hideto
H
Croker
Byron P
BP
Nakagawa
Takahiko
T
D000375:Aging; D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism*; D005089:Exocytosis; D015971:Gene Expression Regulation, Enzymologic; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D019007:P-Selectin / Q000097:blood; D013927:Thrombosis; D057049:Thrombotic Microangiopathies / Q000378:metabolism*; D020302:Weibel-Palade Bodies / Q000473:pathology; D014841:von Willebrand Factor / Q000378:metabolism*
D019007:P-Selectin; D014841:von Willebrand Factor; D052250:Nitric Oxide Synthase Type III