Nitric oxide (NO), an L-arginine derivative, exerts a variety of renal and extrarenal physiological and pathophysiological effects. NO is generated by three isoforms of nitric oxide synthases (NOS): two acutely responsive, constitutive isoforms, neuronal NOS (nNOS) and endothelial NOS (ecNOS), and the slower, more persistent, inducible NOS (iNOS). NO regulates glomerular ultrafiltration; tubular reabsorption, and intrarenal renin secretion. A number of recent studies, most of them in the experimental model of renal mass reduction (RMR) in rats, have raised the hypothesis that an impaired NO synthetic pathway could have a key role in mediating the complex renal hemodynamic and nonhemodynamic disorders associated with the progression of renal disease. Thus, kidneys from rats with RMR produce less NO than normal rats, and NO generation negatively correlates with markers of renal damage. The abnormality is due to a defect in iNOS in the kidney. Data are also available showing that drugs capable of enhancing renal NO activity may be renoprotective in a variety of experimental renal diseases, particularly those characterized by derangements of glomerular hemodynamics. Fewer studies are available in humans and these have shown less than conclusive results.

Animals↗

PubMedDate not supplied

Prevention of renal injury in diabetic MWF rats by angiotensin II antagonism.

We studied the effect of the combination of streptozotocin-induced diabetes and spontaneous renal injury in male MWF rats. Renal hemodynamics was studied by micropuncture 1 month after streptozotocin administration, and kidney morphological evaluation was performed after 4 months of diabetes. We also studied the effect of angiotensin II antagonism on development of renal lesions. Untreated animals developed mild hypertension, proteinuria, and glomerulosclerosis. Induction of diabetes, and maintenance of a moderate hyperglycemic state, was associated with slight but significant elevation in systemic and glomerular capillary blood pressure. Development of proteinuria was not accelerated or exacerbated by diabetes. Glomerular and tubular structural changes were also not worsened by diabetes. Antihypertensive treatment with an ACE inhibitor (benazepril) or with an AII receptor antagonist (valsartan) almost completely prevented systemic and glomerular capillary hypertension, proteinuria and renal structural changes. No significant differences in glomerular volume were observed among the four groups. That induction of experimental diabetes, although associated with glomerular capillary hypertension, did not aggravate the rate of progression of renal dysfunction would suggest that glomerular injury is not directly influenced by glomerular hemodynamic conditions in these animals. Prevention of renal functional and structural abnormalities by antagonism of AII activity in diabetic MWF rats suggests a pathogenetic role for angiotensin in inducing the renal disease in these animals.

Angiotensin II↗

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Angiotensin II blockade limits tubular protein overreabsorption and the consequent upregulation of endothelin 1 gene in experimental membranous nephropathy.

Proteinuric renal diseases are associated with excessive renal synthesis of endothelin 1 (ET-1) either in experimental animals or humans. This has been interpreted as an upregulation of ET-1 gene in proximal tubular cells secondary to overreabsorption of an unusual amount of filtered proteins. Here we used a model of chronic proteinuria, passive Heymann nephritis (PHN), to localize the structure of the kidney responsible for excessive ET-1 expression and synthesis and to clarify whether drugs that reduce glomerular protein trafficking modified the distribution of ET-1 mRNA and the corresponding peptide in the kidney. PHN was induced in Sprague-Dawley rats after injection of rabbit anti-Fx1A antibody. Group 1 (n = 5) was untreated, group 2 (n = 5) was given daily the angiotensin-converting enzyme inhibitor lisinopril (40 mg/l) plus the angiotensin II receptor antagonist L-158,809 (50 mg/l) from day 7--when rats were already proteinuric--to month 12. An additional group of normal rats (n = 5) was used as controls. Urinary excretion of ET-1 was significantly increased in PHN rats as compared with controls and normalized by the treatment. By in situ hybridization a weak signal for ET-1 mRNA was detectable in glomeruli, distal tubular segments, and proximal tubules of control kidneys. By contrast, a strong labeling was found in the kidneys of rats with PHN which was mainly localized to proximal tubules and renal interstitium. The pattern of renal ET-1-like immunoreactivity was remarkably consistent with ET-1 mRNA expression. In animals with PHN given the angiotensin II blocking therapy, the urinary excretion of proteins normalized, and the structural integrity of the kidney was well preserved. In the kidney tissue taken from these animals, both ET-1 mRNA and protein staining were quite comparable to controls. These data suggest a link between excessive protein tubular reabsorption and enhanced renal ET-1 in chronic nephropathies and provide a novel explanation for the renoprotective effect in vivo of drugs that, by blocking the biological activity of angiotensin II, reduce glomerular protein traffic and possible deleterious effects of excessive tubular protein overloading.

Angiotensin II↗

PubMedDate not supplied

Protein overload activates proximal tubular cells to release vasoactive and inflammatory mediators.

Chronic renal diseases with highly enhanced glomerular permeability to proteins are accompanied by tubulointerstitial inflammation and scarring and progression to renal failure. As a consequence of increased glomerular permeability, proteins filtered through the glomerular capillary in excessive amount have intrinsic renal toxicity at least partially linked to their accumulation in the proximal tubular cell cytoplasm during the process of reabsorption along the nephron. Experimental evidence is available showing that protein overload per se activates proximal tubular epithelial cells in culture to upregulate genes encoding for endothelin, chemokines and cytokines. These vasoactive and inflammatory substances, formed in excessive quantities by the tubular cells, are released mainly into the basolateral compartment, a pattern of secretion that in the kidney would favor recruitment and activation of inflammatory cells into the renal interstitium and fibrogenic reaction leading to renal scarring.

Absorption↗

PubMedDate not supplied

Nitric oxide/L-arginine in uremia.

Nitric oxide (NO), a gaseous free radical derived from L-arginine, is a potent modulator of vascular tone and platelet functions. A number of recent studies, both in the experimental model of renal mass reduction (RMR) in rats and in uremic patients, have raised the hypothesis that abnormalities of NO synthetic pathway could have a key role in mediating the complex hemodynamic and hemostatic disorders associated to the progression of renal disease. Thus, kidneys from rats with RMR produce less NO than normal rats and NO generation negatively correlates with markers of renal damage. The abnormality is due to a strong defect of inducible NO synthase (iNOS) content in the kidney. Recent in vitro and in vivo data have raised the possibility that excessive renal synthesis of the potent vasoconstrictor and promitogenic peptide endothelin-1 (ET-1) is a major determinant for progressive iNOS loss in the kidney of RMR rats. In contrast, uremia is associated with excessive systemic NO release, both in experimental model and in human beings. In the systemic circulation of uremic rats, as well as uremic patients, NO is formed in excessive amounts. Possible cause of the increased NO levels is higher release from systemic vessels due to the augmented expression of both iNOS and endothelial NOS. A putative cause for excessive NO production in uremia can be guanidinosuccinate, an uremic toxin that accumulates in the circulation of uremic patients and upregulates NO synthesis from cultured endothelial cells. Upregulation of systemic NO synthesis might be a 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.

Animals↗

PubMedDate not supplied

Interleukin-1 and glomerular mesangial cells.

Our previous in vitro study demonstrated that interleukin-1 (IL-1) stimulates gene expression and production of leukocyte chemotactic factors, colony-stimulating factors and interleukin-6 in human mesangial cells in culture. Here we investigated whether IL-1 regulates its own gene expression in human mesangial cells. Northern blot experiments showed that IL-1 induced IL-1 mRNA expression in a dose-dependent manner. The action of IL-1 on mesangial cells was mediated through the IL-1 receptor type I, which is constitutively expressed by mesangial cells. Recombinant IL-1 receptor antagonist blocked the IL-1 mRNA as well as interleukin-6 and interleukin-8 gene expression induced by IL-1. These data support the crucial role played by IL-1 in regulating mesangial cell cytokine genes within the glomerulus during immunological or inflammatory processes.

Blotting, Northern↗

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Reduced fibrinolytic activity in glomeruli isolated from rabbits infused with tumor necrosis factor.

Glomerular fibrin deposition may result from local activation of blood coagulation and/or impaired removal by the fibrinolytic system. We evaluated the fibrinolytic activity of glomeruli isolated from rabbits infused for 5 h with tumor necrosis factor (TNF) at the doses of 0.8 micrograms/kg/h (n = 5) and 8 micrograms/kg/h (n = 3) or with endotoxin (8 micrograms/kg/h, n = 7). Animals infused with vehicle (n = 11) served as control group. Plasminogen activator (PA) activity of glomerular extracts from rabbits infused with 8 micrograms/kg/h of TNF or endotoxin was significantly lower than that of samples from control animals (p = 0.013 and p = 0.003, respectively). At the dose of 0.8 micrograms/kg/h, TNF caused a reduction in glomerular PA activity which, however, did not reach statistical significance. Neither plasminogen-independent activity nor PA inhibitor activity was detected in glomerular extracts. Fibrin autography of control extracts revealed the presence of two main fibrinolytic activities comigrating with purified urokinase-type and tissue-type PAs. In treated samples, the bands corresponding to free PAs were markedly reduced, with no evidence of enzyme-inhibitor complex formation. Local reduction of fibrinolytic capacity may contribute to intraglomerular fibrin deposition during endotoxemia or in renal inflammatory diseases associated with TNF production.

Animals↗

PubMedDate not supplied

Pathophysiology and management of thrombotic microangiopathies.

Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are syndromes of microangiopathic hemolytic anemia, and thrombocytopenia in which endothelial dysfunction appears to be an important factor in the sequence of events leading to microvascular thrombosis. They are termed thrombotic microangiopathies (TMA). Differentiation of the several primary forms of TMA is crucial to predict disease outcome and to establish the most appropriate therapeutic approach. Typical verotoxin-associated HUS, mostly due to E.coli O157:H7 infection, is associated with prodromal diarrhea followed by acute renal failure, and considered a disease with a good outcome. Antibiotics are not necessary and antimotility agents are contraindicated. No specific therapies aimed at preventing or limiting the microangiopathic process have been proved to affect the course of the disease in children. Atypic HUS covers two clinical conditions: one characterized by severe gastrointestinal prodromes, acute onset anuria, and neurological involvement, and associated to high mortality rate; the second form without diarrhea prodromes but with progressive renal function deterioration and neurological involvement that resembles TTP. Supportive therapy is required in the diarrhea-associated form, while more specific therapies are needed in the latter form. Neurological symptoms usually dominate the clinical picture of acute TTP. Infusion or exchange of fresh frozen plasma have dramatically changed the outcome of a disease that in the sixties was almost invariably fatal. Relapsing episodes of TTP are being reported increasingly often because more patients recover from the initial acute episode thanks to improved treatments. Plasma infusion has been extensively used for this form of TTP, and remission of relapsing episodes documented in most cases. Plasma-resistant HUS or TTP have invariably a poor outcome if alternative treatments are not effective. Bilateral nephrectomy may be an effective rescue therapy for patients who failed to respond to plasma. Familial HUS/TTP is a form of TMA with recessive or dominant inheritance of unknown pathogenesis. The outcome is usually poor. In summary, a general consensus has been achieved that therapies (i.e. plasma exchange or infusion) aimed at stopping the microangiopathic process should always be tried in TTP and in adult and/or atypical forms of HUS to minimize the risk of death or long-term sequela. This approach is seldom effective in secondary forms whose outcome mainly depends on the prognosis of the underlying condition, and is not risk-effective in typical childhood HUS, that usually recovers spontaneously.

Acute Disease↗

PubMedDate not supplied

How much must blood pressure be reduced in order to obtain the remission of chronic renal disease?

Most chronic nephropathies are characterized by a progressive decline in glomerular filtration rate (GFR) that may lead to renal function replacement by dialysis or transplant. Hypertension has an extremely important role among the various mechanisms contributing to renal function deterioration. High blood pressure levels are associated with increased urinary excretion of proteins and the decrease of systemic and glomerular hypertension reduces urinary excretion of proteins and preserves renal function deterioration. Moreover, recent studies found that an intensified blood pressure control (less than 130/80 mmHg) can slow the progression of diabetic and non diabetic renal disease even more than conventional blood pressure control. The Ramipril Efficacy in Nephropathy (REIN) Study showed that ramipril, an ACE-inhibitor, slowed the rate of GFR decline and halved the combined risk of doubling serum creatinine or end stage renal failure (ESRF) in patients with nephrotic range proteinuria as compared to conventional antihypertensive therapy, at comparable levels of blood pressure control. In these patients, prolonged enough treatment (at least 36 months) with ramipril, lowered the velocity of GFR decline and reduced the risk of dialysis. Thus, both tight blood pressure control and ACE-inhibitors may have a renoprotective effect. It will be interesting to evaluate whether the two combined approaches may have sinergistic effects.

Angiotensin-Converting Enzyme Inhibitors↗