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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.

Original publication




Journal article


Am J Physiol Renal Physiol

Publication Date





F1402 - F1408


Acute Kidney Injury, Animals, Blotting, Western, Cell Count, Cyclic GMP-Dependent Protein Kinases, DNA, Endothelium, Hypertrophy, Kidney, Kidney Tubules, Proximal, Mice, Mice, Inbred C57BL, Mice, Knockout, Nephrectomy, Nitric Oxide, Nitric Oxide Donors, Nitric Oxide Synthase Type III, Paraffin Embedding, Protein Biosynthesis, RNA, Renal Circulation, Signal Transduction, TOR Serine-Threonine Kinases