Renal and systemic nitric oxide synthesis in rats with renal mass reduction

Abstract

In rats undergoing renal mass reduction (RMR) oral supplementation with the nitric oxide (NO) precursor L-arginine increases glomerular filtration rate and ameliorates signs of glomerular injury, suggesting that chronic renal failure in the rats is a condition of low NO formation in the kidney. On the contrary, data are available that in the systemic circulation of uremics, both rats and human beings, NO is formed in excessive amounts and may contribute to platelet dysfunction and bleeding tendency, well-known complications of uremia. The present study was designed to clarify the pathophysiology of renal and systemic NO synthesis in uremia. We showed that renal ex vivo NO generation, measured as the conversion of [3H] L-arginine to [3H] L-citrulline, was lower than normal in RMR rats, seven days after surgery, and progressively worsened with time in close correlation with signs of renal injury. Consistent with these results, urinary excretion of the stable NO metabolites, NO2-/NO3-, significantly decreased in rats with RMR. To go deeper into the cellular origin and biochemical nature of this abnormality we used two histochemical approaches that could locate either NO synthase (NOS) catalytic activity (NADPH-diaphorase) or NOS isoenzyme expression (immunoperoxidase). NADPH-diaphorase documented a progressive loss of renal NOS activity in RMR rats that co-localized with a strong progressive decrease of inducible NOS isoenzyme (iNOS) immunostaining. At variance with iNOS, endothelial cell NOS (ecNOS) staining was rather comparable in RMR and control kidneys. At variance to the kidney, in the systemic circulation of RMR rats the synthesis of NO increased as reflected by higher than normal plasma NO2-/NO3- concentrations. High systemic NO likely derives from vessels as documented by the increased NOS activity and higher expression of both iNOS and ecNOS in the aorta of RMR rats. Up-regulation of systemic NO synthesis might be an early defense mechanism against hypertension of uremia. On the other hand, more NO available to circulating cells may sustain the bleeding tendency, a well-known complication of uremia.

Role of Nitric Oxide–Producing and–Degrading Pathways in Coronary Endothelial Dysfunction in Chronic Kidney Disease

“…Paradoxic, previous studies showed elevated plasma NOx levels in patients with CKD, which was probably due to decreased excretion of NOx (46,47). To the extent that pulsatile stretch and distension of the arterial wall favor NO release in hypertension (48), it is speculated that lack of hypertension in our canine model and the subsequent reduction in systemic NO production may result in no increases in plasma NOx levels. Of note, in mild (i.e., 1/2Nx) CKD, the eNOS expression was relatively preserved, whereas the DDAH-II expression was markedly downregulated (Figure 3).…”

Vascular Endothelin-1 Gene Expression and Synthesis and Effect on Renal Type I Collagen Synthesis and Nephroangiosclerosis During Nitric Oxide Synthase Inhibition in Rats

“…21 In addition, antagonism of endothelin receptors delayed the progression of renal failure, as evidenced by measurement of urinary protein and histological analysis, and increased the survival rate of rats with renal mass reduction, 39 a model characterized by an impairment of renal NO production. 40 In conclusion, our study establishes that, in preglomerular vessels, endogenous NO not only acts as a vasodilatory autacoid but also prevents the pathogenic activity of ET-1. This effect of NO is at least partially due to the inhibition of vascular ET-1 synthesis.…”

Evidence for the Existence of Two Distinct Functions for the Inducible NO Synthase in the Rat Kidney

“…In addition, deficient NO production has been described in Nx rats and could contribute to renal injury in this model (11)(12)(13). Although these data are interpreted by several investigators as indicative that progressive renal disease is a state of NO deficiency (11)(12)(13), the role of NO derived from the inducible isoform, iNOS, remains uncertain.…”

“…In addition, deficient NO production has been described in Nx rats and could contribute to renal injury in this model (11)(12)(13). Although these data are interpreted by several investigators as indicative that progressive renal disease is a state of NO deficiency (11)(12)(13), the role of NO derived from the inducible isoform, iNOS, remains uncertain. Several studies indicated that iNOS is expressed in large amounts in the normal renal tissue, localizing mainly in the tubules, and that pathologic conditions, such as clinical and experimental chronic renal insufficiency, are associated with marked iNOS downregulation (13)(14)(15).…”