title: Endothelial dysfunction promotes the transition from compensatory renal hypertrophy to kidney injury after unilateral nephrectomy in mice.
abstract: Loss of functional nephrons associated with chronic kidney disease induces glomerular hyperfiltration and compensatory renal hypertrophy. We hypothesized that the endothelial nitric oxide synthase (eNOS) [soluble guanylate cyclase (sGC)] protein kinase G (PKG) pathway plays an important role in compensatory renal hypertrophy after unilateral nephrectomy. Analysis of mice subjected to unilateral nephrectomy showed increases in kidney weight-to-body weight and total protein-to-DNA ratios in wild-type but not eNOS knockout (eNOSKO) mice. Serum creatinine and blood urea nitrogen increased after nephrectomy in eNOSKO but not in wild-type mice. Furthermore, Bay 41-2272, an sGC stimulator, induced compensatory renal hypertrophy in eNOSKO mice and rescued renal function. The NO donor S-nitrosoglutathione (GSNO) and Bay 41-2272 stimulated PKG activity and induced phosphorylation of Akt protein in human proximal tubular cells. GSNO also induced phosphorylation of eukaryotic initiation factor 4E-binding protein and ribosomal protein S6. Our results highlight the importance of the eNOS-NO-PKG pathway in compensatory renal hypertrophy and suggest that reduced eNOS-NO bioavailability due to endothelial dysfunction is the underlying mechanism of failure of compensatory hypertrophy and acceleration of progressive renal dysfunction.
authors.affiliation: Department of Nephrology and Hypertension, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, Japan. zajiten.1@med.kawasaki-m.ac.jp
authors.forename: Hajime
authors.initials: H
authors.lastname: Nagasu
authors.forename: Minoru
authors.initials: M
authors.lastname: Satoh
authors.forename: Kengo
authors.initials: K
authors.lastname: Kidokoro
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nishi
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
authors.forename: Tamaki
authors.initials: T
authors.lastname: Sasaki
authors.forename: Naoki
authors.initials: N
authors.lastname: Kashihara
mesh_terms: D058186:Acute Kidney Injury / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004727:Endothelium / Q000201:enzymology / Q000502:physiology*; D006984:Hypertrophy; D007668:Kidney / Q000201:enzymology / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009392:Nephrectomy; D009569:Nitric Oxide / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D016612:Paraffin Embedding; D014176:Protein Biosynthesis; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D012079:Renal Circulation; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D012313:RNA; D004247:DNA; D052250:Nitric Oxide Synthase Type III; D058570:TOR Serine-Threonine Kinases; D017869:Cyclic GMP-Dependent Protein Kinases