Lack of endothelial nitric-oxide synthase leads to progressive focal renal injury.
Because endothelial nitric-oxide synthase (eNOS) is generally considered protective against renal injury, we examined eNOS knockout mice for kidney pathology. In 80% of the adults examined, the renal surface was marked by distinct indented scars containing crowded small glomeruli but lacking attached tubules. Although vasculature was intact in the scars, Bowman's space was dilated and glomerular tufts were degenerated. The atubular glomeruli were embedded in a dense interstitial matrix composed of cells positive for fibroblast (FSP-1) or macrophage (F4/80) markers, degenerated proximal tubules and collecting ducts, and diffuse fibrotic deposits. Surrounding regions of kidney contained mostly normal-appearing tubules, but enlarged or sclerotic glomeruli were also present. In neonatal animals, apoptosis and necrosis were concentrated in tubules within focal parenchymal zones, with narrowing of the glomerulotubular "neck." In summary, targeted deletion of eNOS in mice leads to progressive focal renal abnormalities, including glomerular hypoplasia, and tubular cell death, leading to separation of glomeruli from tubules and tubular disruption. These abnormalities begin developing during the normal up-regulation of eNOS in the maturing kidney and are similar to those of a variety of chronic renal disorders. Endogenous renal eNOS production therefore seems critical for the maintenance of nephron maturation and integrity.
Forbes
Michael S
MS
Department of Pediatrics, University of Virginia, Box 800386, Charlottesville, VA 22908, USA.
Thornhill
Barbara A
BA
Park
Matthew H
MH
Chevalier
Robert L
RL
D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D007150:Immunohistochemistry; D007668:Kidney / Q000201:enzymology / Q000254:growth & development / Q000473:pathology; D007674:Kidney Diseases / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins
D002135:Calcium-Binding Proteins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse