ISSN:1420-4096    

DOI:10.1159/000173397

出版商:S. Karger AG    

年代:1991

数据来源: Karger

ISSN:1420-4096    

DOI:10.1159/000173398

出版商:S. Karger AG    

年代:1991

数据来源: Karger

ISSN:1420-4096    

DOI:10.1159/000173399

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

Previous physiological and biochemical studies suggest the existence of an endogenous renin-angiotensin system (RAS) in the kidney. However, these data cannot exclude the contribution of the circulating RAS. Proof of the local synthesis of RAS components in the kidney has been obtained recently through the use of molecular biological techniques. Using Northern blot analysis, we have demonstrated the intrarenal expression of renin, angiotensinogen, and angiotensin-converting enzyme messenger RNAs. Employing in situ hybridization histochemistry, we have localized the intrarenal tissue sites of renin and angiotensinogen messenger RNA synthesis. Renin gene expression was found in cells of the juxtaglomerular apparatus. Angiotensinogen mRNA was primarily produced in the proximal convoluted tubule with lesser amounts in glomerular tufts and vasculature. These findings led us to hypothesize that the proximal tubule is a major site of renal Ang II synthesis and that locally synthesized Ang II might directly modulate tubular function. Both genes are subject to feedback regulation. Our studies showed that Ang II exerted a stimulatory effect on angiotensinogen but a negative feedback effect on renin gene expression. Dietary NaCl restriction stimulated the expression of both genes, although the onset of renin gene activation required more prolonged sodium chloride restriction. Furthermore, our data indicated that the sodium cation, irrespective of the anion, was primarily important in regulating renal angiotensinogen mRNA levels. Our studies also showed altered intrarenal renin or angiotensinogen expressions in pathophysiological states, e.g. in experimental heart failure and the spontaneously hypertensive rat. Taken together, these data support the existence of a intrarenal RAS and suggest its potential roles in the regulation of renal function in health and disease.

ISSN:1420-4096    

DOI:10.1159/000173400

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

There is growing recognition that angiotensin II (ANG II) formed intrarenally exerts direct effects on renal hemodynamics and tubular reabsorption. In vivo micropuncture experiments performed in anesthetized rats have shown that peritubular capillary infusion of either ANG II or angiotensin I (ANG I), at rates that do not markedly influence baseline vascular resistance, can increase proximal tubular reabsorption rate and enhance the responsiveness of the tubuloglomerular feedback mechanism. With higher ANG II or ANG I infusion rates, pronounced preglomerular vasoconstriction occurs, resulting in reduced glomerular capillary pressure and single nephron glomerular filtration rate. The effects of peritubular capillary infusion of ANG I on glomerular function have been shown to be inhibited by the ANG II receptor antagonist, saralasin, indicating that the observed effects of ANG I on proximal tubular reabsorption and glomerular function are not due to direct effects of the decapeptide but are mediated by increases in the interstitial ANG II concentrations resulting from intrarenally generated ANG II. Interestingly, neither peritubular capillary infusion nor systemic administration of large doses of the angiotensin-converting enzyme (ACE) inhibitor, enalaprilat, elicited significant blockade of the single nephron hemodynamic responses to peritubular infusion of ANG I. These findings indicate that intrarenal conversion of ANG I to ANG II occurs, at least in part, at a site which is inaccessible to acutely administered ACE inhibitors, or that there is an alternative pathway for the intrarenal conversion of ANG I to ANG II that is not blocked by ACE inhibitors.

ISSN:1420-4096    

DOI:10.1159/000173401

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

The technique of perfusing isolated tubular segments from rabbit kidneys was used to study macula densa (MD) control of renin secretion. Renin secretion was found to be markedly and reversibly increased when perfusate NaCl concentration was reduced. This response of renin secretion occurred within the physiological concentration range, i.e. between 80 and 20 mM. The stimulatory effect of reduced NaCl was seen even when total solute concentration was kept constant. In this preparation a reduction of NaCl concentration was a stronger stimulus than a fall in NaCl load. Loop diuretics were found to stimulate renin secretion. Suppression of renin secretion was seen when most of the Na was replaced by Rb or choline, but not when Cl was replaced with isethionate or acetate. Activation of adenosine-1-receptors inhibited MD-stimulated renin secretion, an effect that was blocked by an A1-antagonist. This agent partially blocked NaCl-induced inhibition of renin release, suggesting a possible role of adenosine in MD control of renin secretion.

ISSN:1420-4096    

DOI:10.1159/000173402

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

Angiotensin II (All) has many of the features of the archetypical growth factors and appears to be a growth regulator in the kidney. All binds to specific cell surface receptors present on a number of different renal cell types including mesangial, vascular smooth muscle, tubular and interstitial cells, and activates many of the intracellular signalling pathways associated with cell growth. In vitro All can potentiate the mitogenic effect of other growth factors such as EGF. All induces hypertrophy of vascular smooth muscle cells but the role of All in the growth of other renal cell types has not been systematically studied.

ISSN:1420-4096    

DOI:10.1159/000173403

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

Studies using conventional and patch-clamp microelectrode techniques demonstrate that in a number of cell types angiotensin II (All) causes reversible changes in transmembrane ionic currents, and that these effects can be mimicked by various membrane-associated and cytosolic messengers. All modulates the current amplitude of ion channels, as well as their activation threshold and their open/closed time probability. Stimulatory and inhibitory effects on ion channel activity are a fundamental feature of the development of All actions on target organs.

ISSN:1420-4096    

DOI:10.1159/000173404

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

Angiotensin II (Angll) is a potent regulator of electrolyte transport with biphasic effects on salt and HCO3-resorption in proximal tubule epithelia (PCT). In cultured PCT cells, pM to nM Angll activates a GTP-binding protein to inhibit cAMP formation and thus releases inhibition of apical Na/H exchange. Phospholipase A2 is activated by nM to µM Angll releasing arachidonate which is metabolized by a novel P450 epoxygenase to form 5,6-epoxy-eicosatrienoic acid (5,6-EET). 5,6-EET and nM apical Angll cause dihydropyridine-sensitive Ca2+ influx from the extracellular space, inhibition of apical-to-basolateral Na flux, and decrease in epithelial monolayer short circuit current. 5,6-EET also inhibits Na/K-ATPase by 50%. This P450 epoxygenase is physiologically important in the AngII -signaling system because the P450 inhibitor ketoconazole blocks Angll effects while potentiating exogenous 5,6-EET effects. Finally, these AngII-mediated signaling systems are polarized in the PCT with pM basolateral Angll inhibiting adenylate cyclase and nM apical Angll activating PLA2 and subsequent generation of 5,6-EET

ISSN:1420-4096    

DOI:10.1159/000173405

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

As a target site for angiotensin II (A-II), renal proximal tubule is unique in that it may be equipped with a local A-II generating system and that both basolateral and apical membranes may be accessible for A-II’s action. We have recently conducted studies to examine these possibilities. With in vitro cultured proximal tubular cells, we have demonstrated de novo synthesis of angiotensinogen and renin. With isolated renal brush border membrane (BBM), we have confirmed the presence of A-II receptors and found that A-II directly stimulated BBM Na+-H+ exchange. In search of the signal transduction mechanism, we have found that A-II also activated BBM phospholipase A2 (PLA) and that BBM contained a pertussis toxin-sensitive guanine nucleotide binding protein (G-protein) which mediates the effects of A-II. Further studies showed that prevention of PLA activation abolished A-II’s effect on Na+ – H+ exchange, and that activation of PLA by mellitin and addition of arachidonic acid similarly enhanced Na+-H+ exchange activity, suggesting that PLA activation may mediate the stimulatory effect of A-IIon Na+-H+ exchange. These results thus indicate that a local signal transduction mechanism involving G-protein mediated PLA activation exists in renal BBM which mediates A-II’s effect on Na+-H+ exchange. Taken together, we propose that, independent of A-II in the circulation, local luminal A-II may serve as an important regulatory system on sodium transport in renal proximal

ISSN:1420-4096    

DOI:10.1159/000173406

出版商:S. Karger AG    

年代:1991

数据来源: Karger