Porphyria cutanea tarda, hepatitis C, uroporphyrinogen decarboxylase and mutations of HFE gene. A case-control study.

BACKGROUND: Hemochromatosis gene (HFE) mutations and the hepatitis C virus (HCV) are known risk factors for porphyria cutanea tarda (PCT), but interactions with erythrocytic uroporphyrinogen decarboxylase (UROD) have seldom been addressed. OBJECTIVE: In order to examine the links between these factors, we conducted a multicentre prospective case-control study. METHODS: PCT patients with (n = 32) or without HCV (n = 28) were matched to HCV+ (n = 32) and HCV- controls (n = 28). HFE mutations (C282Y and H63D) were analyzed by PCR. RESULTS: PCT+/HCV+ patients were younger than PCT+/HCV- patients (46.9 vs. 58.2 years, p < 0.001). UROD values were not significantly different in HCV+ and HCV- patients. Both C282Y and H63D were more frequent in PCT+ patients than in controls, but there was no difference in HFE genotype according to HCV seropositivity. Mean UROD was lower in case of HFE mutations in both PCT patients and controls. CONCLUSION: In French patients, HCV infection is probably the major causal factor of PCT. It is not linked with HFE mutations, although they are significantly associated with PCT. A low erythrocytic UROD might be a predisposing factor. The UROD value was lower in patients with HFE mutations, suggesting a possible interaction between HFE genotype and UROD levels.

Intravenous delivery of PTH/PTHrP type 1 receptor cDNA to rats decreases heart rate, blood pressure, renal tone, renin angiotensin system, and stress-induced cardiovascular responses.

While parathyroid hormone type 1 receptor (PTH1R)-mediated vasodilatory, cardiac stimulatory, and renin-activating effects of exogenous PTH/PTH-related protein (PTHrP) are acknowledged, interactions of endogenous PTHrP with these systems remain unclear, mainly because the unavailability of viable PTHrP/PTH1R knockout mice. Transgenic mice overexpressing PTH1R in smooth muscle strongly have supported the PTHrP/PTH1R system as a cardiovascular system (CVS) regulator, but the consequences on renovascular (RVS) and renin-angiotensin systems (RAS) have not been explored in these studies. The aim was to develop a model in which one could study the consequences on CVS, RVS, and RAS of generalized PTH1R overexpression. Systemic PTH1R cDNA plasmid delivery was used in adult rats, a system that is amenable to studies in isolated perfused kidneys and that minimizes development-induced compensatory mechanisms. Intravenous administration of hPTH1R or green fluorescence protein-tagged hPTH1R in pcDNA3 resulted 3 wk later, in generalized expression of hPTH1R (mRNA and protein), especially in vessels, liver, heart, kidney, and central nervous system, where it is expressed physiologically. As expected, PTH1R overexpression decreased BP and renal tone. Unexpected, however, PTH1R overexpression decreased heart rate. These studies also revealed that endogenous PTHrP actually inhibits renin release and that hPTH1R overexpression tends to increase that effect. Striking, liver production and circulatory level of angiotensinogen and hence plasma renin activity were markedly reduced. Thus, abrupt PTH1R overexpression in adult rats profoundly alters the CVS, RVS, and RAS, strongly supporting the PTH/PTHrP/PTH1R system as crucial for heart and vascular tone regulation. In addition, these results revealed that PTH1R-mediated mechanisms might have protective effects against cardiovascular stress-induced responses, including stimulations in heart rate and RAS.

Differential regulation of collecting duct Na+, K+-ATPase and K+ excretion by furosemide and piretanide: role of bradykinin.

In response to chronic treatment with furosemide, collecting ducts adapt their function to the initial loss of Na+ to prevent further Na+ loss and extracellular volume decrease. This adaptation, which includes the overexpression of Na+, K+-ATPase, is thought to account for most of the kaliuretic effect of furosemide. Because piretanide is reported to be less kaliuretic than equidiuretic doses of furosemide, the authors compared the effects of 1-wk treatment with the two loop diuretics on urinary potassium excretion and on Na+, K+-ATPase activity in the collecting duct. At equidiuretic and equinatriuretic doses, furosemide increased urinary potassium excretion as well as collecting duct Na+, K+-ATPase activity, whereas piretanide had no effect on either parameter. These effects of furosemide were curtailed by concomitant administration of the angiotensin-converting enzyme inhibitor enalapril, but they were not altered either by clamping changes in plasma aldosterone or by blocking type I angiotensin receptors. Treatment with the antagonist of bradykinin B2 receptors Hoe140 mimicked the two effects of furosemide. In addition, the effects of Hoe140 and furosemide were not additive. Finally, piretanide increased urinary bradykinin excretion, whereas furosemide did not. These results suggest that induction of collecting duct Na+, K+-ATPase (a) accounts for the kaliuretic effect of furosemide, (b) is independent of the renin/angiotensin/aldosterone system, (c) results from increased Na+ delivery to the collecting duct and enhanced intracellular Na+ concentration, and (d) is prevented in piretanide treated rats by increased bradykinin production that may limit apical Na+ entry in collecting duct principal cells.

Oxytocin-induced renin secretion by denervated kidney in anaesthetized rat.

The effects of oxytocin on renin secretion by denervated kidney were investigated in vivo, by infusing the peptide directly into the renal artery of anaesthetized rats. Renin secretion was calculated by the renal veno-arterial difference in plasma renin activity multiplied by renal plasma flow. The intra-renal arterial (i.r.a.) infusion of oxytocin (1.5 or 15 ng/kg/min, 10 min) induced a sixfold increase in renin secretion as compared to vehicle-treated controls, without effects on renal blood flow, mean arterial blood pressure, glomerular filtration rate or natriuresis. The effect of oxytocin (1.5 ng/kg/min) was prevented by pretreatment with an oxytocin receptor antagonist, desGly-NH(2),d(CH(2))(5)[D-Tyr(2),Thr(4),Orn(8)]vasotocin] (5.6 microg/kg bolus i.v. 20 min before oxytocin infusion, followed by 2.8 microg/kg/min i.r.a.). Nadolol (2.5 mg/kg i.v.), a beta-adrenoceptor antagonist, also blocked the oxytocin-induced increase in renin secretion. These results show that oxytocin is able to stimulate renin release by activating oxytocin receptors but that beta-adrenoceptors also seem to be involved.

Effects of dietary salt changes on renal renin-angiotensin system in rats.

Renin (RA) and angiotensin-converting enzyme (ACE) activities and angiotensinogen, ANG I, and ANG II levels were measured in the kidney (cortex and medulla) and plasma of Wistar-Kyoto rats on a low-sodium (LS; 0.025% NaCl; n = 8), normal-sodium (NS; 1% NaCl; n = 7), or high-sodium (HS; 8% NaCl; n = 7) diet for 21 days. RA, ANG I, and ANG II levels increased in a manner inversely related to sodium content of the diet in both plasma and renal tissues. The LS diet resulted in a 16-, 2.8-, and 1.8-fold increase in plasma RA, ANG I, and ANG II levels, respectively, compared with those in HS rats. In the renal cortex and medulla, RA, ANG I, and ANG II levels were also increased by diminution of dietary salt content but, in contrast to plasma, ANG II levels increased much more than RA or ANG I levels [5.4 (cortex)- and 4.7 (medulla)-fold compared with HS rats]. In summary, we demonstrated variations of ANG II levels in the kidney during dietary salt modifications. Our results confirm that RA and ACE activity are not the steps limiting intrarenal ANG II levels. Nevertheless, despite RA and ACE activity differences between renal cortex and medulla, ANG I and ANG II levels are equivalent in these two tissues; these results argue against a compartmentalization of RAS in these two intrarenal areas.

Contribution of angiotensin II internalization to intrarenal angiotensin II levels in rats.

This study was designed to determine the involvement of AT(1) receptors in the uptake of ANG II in the kidney of rats exposed to differing salt intake. Male Wistar-Kyoto rats were treated with a normal-salt (NS; 1% NaCl, n = 7) or a low-salt (LS; 0.025% NaCl, n = 7) diet combined with (LS+Los, n = 7; NS+Los, n = 7) or without losartan (30 mg. kg(-1). day(-1)), an AT(1) receptor antagonist. Renin (RA) and angiotensin-converting enzyme (ACE) activities and angiotensinogen, ANG I, and ANG II levels were measured in plasma, renal cortex, and medulla. In LS rats, in both plasma and renal cortex, the increase in RA was associated with an increase in ANG I and ANG II levels compared with NS rats, but intrarenal ANG II levels increased more than ANG I levels. In NS+Los rats, the increase in RA in plasma was followed by a marked increase in plasma ANG I and ANG II levels compared with NS rats whereas in the kidney the increase of renal RA was followed by a decrease of the levels of these peptides. The same pattern was observed in LS+Los rats, but the decrease in renal ANG II levels was much more pronounced in LS+Los rats than in NS+Los rats. Our results suggest that the increase in renal ANG II levels after salt restriction results mainly from an uptake of ANG II, via AT(1) receptors. Such elevated intrarenal ANG II levels could contribute to maintain sodium and fluid balance and arterial blood pressure during salt-deficiency states.

Influence of sodium intake on the cardiovascular and renal effects of brain mineralocorticoid receptor blockade in normotensive rats.

OBJECTIVE: We have previously shown that brain mineralocorticoid receptors (MR) participate in the control of arterial pressure and renal excretory function in normotensive rats. In the present study, we evaluate the influence of sodium intake on the control of cardiovascular and renal function by brain MR in normotensive conscious rats. We hypothesize that modulation of sodium intake affects the cardiovascular and renal effects of brain MR blockade. DESIGN AND METHODS: We examined the effect of intracerebroventricular (ICV) administration of MR antagonist (RU28318) on systolic blood pressure (SBP), heart rate, and urinary excretion of water and electrolytes in normotensive Wistar rats subjected to different dietary sodium content. Rats were fed high (8%), normal (0.4%), or depleted (0%) sodium for 3 weeks. SBP and heart rate measurements were performed using an indirect tail cuff method. Metabolic cages were used to assess renal function. RESULTS: ICV injection of 100 ng RU28318 induced a long-lasting decrease ( 0.01) in SBP in rats submitted to different sodium intake. At 8 h, the decrease in SBP did not differ between rats on high (30 +/- 5 mmHg), normal (28 +/- 6 mmHg), and low (21 +/- 3 mmHg) sodium diets. At 24 h, the decrease in SBP was also comparable between rats on different sodium diets. Increased diuresis was observed during the period 0-8 h after ICV injection of RU28318; this was less pronounced in rats on the low sodium diet. Urinary excretions of potassium and chloride were also increased during this period, particularly in rats on the high and normal sodium diets compared with rats with low sodium intake. Urinary excretion of sodium was increased only in the rats fed high and normal sodium diets. Measurement of plasma renin activity, which was suppressed and stimulated, respectively, by high and low sodium intake, indicated that the effects on SBP and renal function induced by ICV RU28318 were independent from the level of activation of the renin-angiotensin system. CONCLUSION: In contrast to our hypothesis, in normotensive Wistar rats, sodium intake does not affect the hypotension induced by brain MR blockade. However, sodium depletion attenuated the renal effects of brain MR blockade.

Effects of brain mineralocorticoid receptor blockade on blood pressure and renal functions in DOCA-salt hypertension.

In normotensive rats, we have previously demonstrated a role of brain mineralocorticoid receptors in blood pressure and renal function control. In the present study, the coordinate cardiovascular and renal effects of brain mineralocorticoid receptor blockade were examined by intracerebroventricular (i.c.v.) administration of a selective mineralocorticoid receptor antagonist (RU28318; 3,3-oxo-7 propyl-17-hydroxy-androstan-4-en-17yl-propionic acid lactone) in rats with hypertension induced by deoxycorticosterone acetate (DOCA) and salt. DOCA pellets were implanted s.c. in male Wistar rats given 0.9% NaCl as drinking solution 3 or 5 weeks before assessment of the effects of i.c.v. injection of RU28318 on cardiovascular and renal functions. Changes in expression of brain angiotensinogen, atrial natriuretic peptide (ANP) and mineralocorticoid receptor mRNA in specific brain areas in 3-week DOCA-salt rats were evaluated by in situ hybridization. The rise in systolic blood pressure induced by DOCA-salt treatment was most marked during the first 3 weeks. At 3 and 5 weeks after implantation of the DOCA-pellets a single i.c.v. injection of 10 ng of RU28318 significantly decreased systolic blood pressure during 24 h as assessed at 2, 8 and 24 h, while heart rate was not altered. Increased urinary excretion of water and electrolytes was observed in 3- and 5-week DOCA-salt rats during the period 0-8 h after i.c.v. injection of RU28318 while the suppressed plasma renin activity was not affected. The expression of brain angiotensinogen, ANP and mineralocorticoid receptor mRNA was not altered by 3-week DOCA-salt treatment, but 3 h after i.c.v. injection of RU28318, mineralocorticoid receptor mRNA expression in hippocampal cell fields responded with an increase of about 40%. In conclusion, these results demonstrate that in rats with hypertension induced by DOCA-salt, brain mineralocorticoid receptor blockade affects renal function and blood pressure regulation.