Blood pressure is frequently elevated, blood volume is usually normal or increased and plasma
renin and
aldosterone are usually low in
nephrotic syndrome (NS). These observations challenge the conventional view attributing
sodium retention in NS to a
hypoalbuminemia-induced intravascular volume contraction. Given the pivotal role of
nitric oxide (NO) in regulation of renal
sodium (Na) handling, vascular resistance and sympathetic activity, we considered that Na retention and
hypertension in NS may be associated with impaired NO system. Urinary excretion of Na and NO metabolites (NOx), as well as immunodetectable endothelial (eNOS), inducible (iNOS) and neuronal (nNOS) NO synthases were determined in rats with
puromycin aminonucleoside (PAN)-induced NS, rats with
protein overload
proteinuria,
Nagase rats (NAR) with inherited analbuminemia, iNOS inhibitor (
aminoguanidine)-treated rats, prenephrotic PAN-treated and placebo-treated control rats. The NS group showed marked
proteinuria,
hypoalbuminemia, decreased fractional excretion of Na (FENa), reduced urinary NOx excretion, and severe reduction of iNOS and nNOS
protein abundance in the kidney. Similar results were found in rats with
protein overload
proteinuria in which
proteinuria was present without
hypoalbuminemia. In contrast, despite extreme
hypoalbuminemia, NAR showed normal FENa, increased urinary NOx excretion and upregulations of iNOS and nNOS
protein abundance in the kidney. Administration of
aminoguanidine for 3 weeks lowered FENa in normal rats to levels approximating those found in the NS group. Animals studied 2 days after PAN administration (wherein
proteinuria was absent) showed no abnormality. Thus, chronic PAN-induced NS results in downregulation of kidney iNOS and nNOS, which can contribute to the reduction of FENa by augmenting renal tubular Na reabsorption, and preglomerular vasoconstriction. Findings in the NAR, which had profound
hypoalbuminemia without
proteinuria, and in rats with
protein overload
proteinuria, which had
proteinuria without
hypoalbuminemia, point to
proteinuria as the primary mediator of kidney iNOS and nNOS deficiency and impaired Na excretion in PAN-induced NS.