Effects of hypoxia on renin secretion and renal renin gene expression

Effects of hypoxia on renin secretion and renal renin gene expression. Plasma renin activity (PRA) and renal renin mRNA levels were measured in male rats exposed to hypoxia (8% O2) or to carbon monoxide (CO; 0.1%) for six hours. PRA increased fourfold and 3.3-fold, and renin mRNA levels increased to 220% and 200% of control, respectively. In primary cultures of renal juxtaglomerular (JG) cells, hypoxia (lowering medium O2 from 20% to 3% or 1%) for 6 or 20hours did not affect renin secretion or gene expression. Renal denervation did not prevent stimulation of the renin system by hypoxia. Because norepinephrine increased 1.7-fold and 3.2-fold and plasma epinephrine increased 3.9-fold and 7.8-fold during hypoxia and CO inhalation, respectively, circulating catecholamines might mediate the stimulatory effects of hypoxia on renin secretion and renin gene expression. Stimulation of β-adrenergic receptors by continuous infusion of 160 μg/kg/hr isoproterenol increased PRA 17-fold and 20-fold after three and six hours, respectively, and renin mRNA by 130% after six hours. In rats with a stimulated renin system (low-sodium diet), isoproterenol did not stimulate PRA or renal renin mRNA further. In summary, both arterial and venous hypoxia can stimulate renin secretion and renin gene expression powerfully in vivo but not in vitro. These effects seem not to be mediated by renal nerves or by a direct effect on JG cells but might be mediated by circulating catecholamines

Extracellular calcium exerts a dual effect on renin secretion from isolated mouse juxtaglomerular cells

Utilizing primary cultures of mouse renal juxtaglomerular cells we found that renin secretion during 20 h of incubation was stimulated by 100% when extracellular calcium was lowered from a basal level of 0.5 mM to below 1 microM, and was enhanced in a concentration-dependent fashion by 600% when extracellular calcium was increased up to 10 mM. The stimulatory effect of low calcium on renin secretion was apparent after the first hour of incubation, whereas the stimulatory effect of increased calcium occurred with a delay of at least 1 h. During the first hour of incubation increased extracellular calcium blunted the stimulation of renin secretion induced by forskolin (10 microM). The stimulatory effect of increased calcium was attenuated in the presence of 8-pCPT-cGMP, a membrane-permeable cGMP analogue, and in the presence of 100 mM sucrose. The stimulatory effect of increased calcium was blunted in the presence of 0.5 mM cobalt, which itself stimulated renin secretion at normal (0.5 mM) calcium concentrations. Renin synthesis by the cultured cells at low calcium was markedly attenuated in proportion with total protein synthesis, whereas renin synthesis was not altered at increased calcium concentrations. Our findings suggest that a rise of intracellular calcium, induced by an increase of extracellular calcium, is associated with a transient inhibition followed by a marked and regulatable stimulation of renin secretion. Neither calcium depletion nor calcium elevation appears to exert specific effects on renin synthesis in juxtaglomerular cells

Renal autacoids are involved in the stimulation of renin gene expression by low perfusion pressure

Renal autacoids are involved in the stimulation of renin gene expression by low perfusion pressure. This study aimed to examine the role of local autacoids for the regulation of renin secretion and renin gene expression by the renal perfusion pressure. To this end the effects of unilateral reduction of renal perfusion by 0.2 mm clips on plasma renin activity and on renal renin mRNA levels were examined in rats treated with the cyclooxygenase inhibitor meclofenamate (8 mg/kg body wt, twice a day), with the NO-synthase inhibitor nitro-L-arginine-methylester (L-NAME, 40 mg/kg body wt, twice a day) or with a combination of both. L-NAME alone decreased basal PRA values from 9.9 to 5.4 ng Ang I/hr times ml, while meclofenamate alone and the combination meclofenamate/L-NAME had no consistent effect on basal PRA. Unilateral renal artery clipping increased PRA values from 9.9 ng Ang I/hr times ml to 34, 27, and 16 ng Ang I/hr times ml in vehicle, meclofenamate, and L-NAME treated animals, respectively, but did not increase PRA in meclofenamate/L-NAME treated rats (9.5 ng Ang I/hr times ml). Renal renin mRNA levels in the clipped kidneys increased 4.8-, 2.6-, 2.5- and 1.8-fold in the clipped kidneys in vehicle, meclofenamate, L-NAME and meclofenamate/L-NAME injected animals, respectively. These findings indicate that both the inhibition of prostaglandin synthesis and of the formation of endothelium-derived relaxing factor (EDRF) attenuate the increase of renin gene expression and of renin secretion in response to acute unilateral renal hypoperfusion and that the effects of both maneuvers are additive. The data suggest that the stimulations of renin gene expression in response to low renal perfusion pressure require both intact prostaglandin and EDRF formation

Endothelium derived relaxing factor is involved in the pressure control of renin gene expression in the kidney

To study the influence of endothelium derived relaxing factor/nitric oxide (EDNO) on renin gene expression, the effects of a 2-day treatment with the NO-synthase inhibitor nitro-L-arginine-methylester (L-NAME, 40 mg/kg twice a day) on plasma renin activity (PRA) and renal and adrenal renin m-RNA levels were examined in conscious rats with and without unilateral renal clips (0.2 mm). In sham-clipped animals L-NAME led to a decrease of PRA from 7.5 to 2.5 ng angiotensin (ANGI).h-1.ml-1 and to a 35% decrease of renal renin m-RNA levels. Unilateral renal artery clipping increased PRA to 35 and to 13 ng ANGI.h-1.ml-1 in vehicle and in L-NAME-treated rats, respectively. In the clipped kidneys renin m-RNA levels increased to 450% of control values in vehicle-treated animals and to 220% of control values in L-NAME-treated animals. In the contralaterals as opposed to clipped kidneys, renin m-RNA levels decreased to 16% and 50% of the control values in vehicle- and in L-NAME-treated animals, respectively. In the adrenal glands renin m-RNA levels were not significantly changed either by clipping of one renal artery or by treatment of animals with L-NAME. The NO-donor sodium nitroprusside (100 microM) was found to increase renin secretion and renin m-RNA levels in primary cultures of renal juxtaglomerular cells. These findings suggest that EDNO is involved in the control of the renin gene by the renal perfusion pressure

Role of the macula densa in the control of renal renin gene expression in two-kidney/one-clip rats

This study was designed to examine whether macula densa function is involved in the changes of renal renin gene expression upon acute hypoperfusion of one kidney. To block macula densa function, rats with free access to salt and water were subcutaneously infused with furosemide (12 mg/day) for 6 days. Then, 4 days after the start of the infusion, the left renal arteries were clipped with 0.2-mm silver clips and renin mRNA levels in ipsilateral and contralateral kidneys, as well as plasma renin activities (PRA), were determined 48 h after clipping. In non-clipped animals furosemide increased PRA from 10 to 47 ng angiotensin I.h-1.ml-1 and raised renin mRNA levels in both kidneys 2.5-fold. In vehicle-infused animals, clipping of the left renal artery increased PRA to 37 ng angiotensin I.h-1.ml-1 and led to a 5-fold rise of renin mRNA levels in the ipsilateral kidneys and to a suppression to 20% of the control values in the contralateral kidneys. PRA values in clipped and furosemide-infused animals were 45 ng angiotensin I.h-1.ml-1. In these animals renin mRNA levels increased in the ipsilateral kidneys to similar absolute values as in vehicle-infused rats, whilst contralateral renin mRNA levels fell to about 25% of the respective controls. These findings indicate that the stimulations of renin gene expression by inhibition of macula densa salt transport and by renal artery clipping are not additive, suggesting that the macula densa mechanism may participate in the stimulation of renin gene expression upon hypoperfusion.(ABSTRACT TRUNCATED AT 250 WORDS

Interrelation between renin mRNA levels, renin secretion, and blood pressure in two-kidney, one clip rats

To examine the interrelation between renin mRNA levels, renin secretion, and blood pressure in rats, we clipped the left renal arteries of rats and measured renin mRNA levels in both kidneys, plasma renin activity, and blood pressure. One and 2 days after clipping, renin mRNA levels increased 3-fold and 4.3-fold in the stenosed kidney and were suppressed to 52% and 26% of controls in the intact kidneys; plasma renin activity increased from 8 to 16.5 and to 30.5 ng angiotensin I.h-1.mL-1 and systolic blood pressure rose from 114 to 123 and to 137 mm Hg. We found a strong correlation (P < .001) between plasma renin activity and renin mRNA levels in the clipped kidneys. We also found significant correlations (P < .05) between mRNA levels in the clipped and intact kidneys and between plasma renin activity and blood pressure for the individual animals. Treatment of normal rats with the converting enzyme inhibitor ramipril (5 mg/kg twice a day) for 2 days increased renin mRNA levels in both kidneys fourfold. In animals with unilateral clips, additional treatment with ramipril increased renin mRNA levels 6.4-fold in the stenosed and 3.3-fold in the intact kidneys. These findings suggest that endogenous angiotensin II exerts an inhibitory effect on renin mRNA expression in normal kidneys, clipped kidneys, and their contralaterals. Suppression of the renin gene in contralateral kidneys seems not to be directly mediated by the rise of plasma renin activity or by the rise of blood pressure in two-kidney, one clip rats

Influence of dietary NaCl intake on renin gene expression in the kidneys and adrenal glands of rats

The aim of this study was to examine the influence of dietary NaCl intake on renin gene expression in the kidneys and adrenal glands of adult rats. Rats were kept on low (0.02%, w/w), normal (0.6%) or high (4%) NaCl diets and plasma renin activity (PRA) and the relative abundance of renin messenger ribonucleic acid (mRNA) in renal and adrenal tissue were followed for 20 days. In animals on a normal-salt diet PRA and renal renin mRNA levels did not change with time. PRA values in animals on the low-salt diet increased transiently (about threefold) and then declined again during the third week of treatment. Renal renin mRNA levels in these animals paralleled the changes of PRA. Conversely, in the animals kept on a high-salt diet PRA values decreased transiently and renal renin mRNA decreased continuously to about 50% of control values. Arterial blood pressure measured in conscious animals was not significantly influenced by the different salt diets. To establish whether the changes in renin mRNA levels are mediated by renal nerve input, animals on the different diets were also studied after unilateral renal denervation. Renal nerve section led to a 50% decrease of renin mRNA levels in the denervated kidneys in animals kept on the normal-salt diet. In the animals on the low-salt diet renin mRNA rose to similar levels in the denervated to those in the innervated kidney, while in animals receiving a high-salt diet renin mRNA was further decreased in the denervated kidneys.(ABSTRACT TRUNCATED AT 250 WORDS