Nitric oxide generated by nNOS in the macula densa regulates the afferent arteriolar diameter in rat kidney

Nitric oxide (NO) derived from neuronal NO synthase (nNOS) in the macula densa is a modulator of tubuloglomerular feedback. However, little is known about the regulation of the afferent arteriolar diameter by NO from the macula densa in salt-sensitive hypertension. We investigated the relationship between nNOS in the macula densa and the afferent arteriolar diameter in deoxycorticosterone acetate (DOCA)-salt hypertensive rats treated with angiotensin converting enzyme (ACE) inhibitor or thiazide for 5 weeks. DOCA rats had reduced nNOS expression in the macula densa compared to controls and reduction of NO production evaluated with 4,5-diaminofluorescein diacetate in the juxtaglomerular apparatus (JGA). Treatment with ACE inhibitor and thiazide increased nNOS and NO production in the JGA. The diameter of the afferent arteriole observed by SEM using microvascular casts was smaller in DOCA rats compared to control rats, and ACE inhibitor or thiazide dilated the afferent arteriole with a positive correlation to nNOS immunoreactivity in the macula densa. In conclusion, the afferent arteriolar diameter might be regulated by NO derived from nNOS in the macula densa in DOCA-salt hypertensive rats.     

Role of macula densa neuronal nitric oxide synthase in renal diseases

Macula densa cells have an important role in the regulation of glomerular blood flow and glomerular filtration by its regulation of afferent arteriolar vascular tone. Nitric oxide derived from neuronal nitric oxide synthase (nNOS) in macula densa can dilate afferent arterioles. Macula densa nNOS is important for renin secretion, and its expression is regulated by dietary salt, renal angiotensin II, intracellular pH, and other factors. In salt-sensitive hypertension, nNOS is suppressed, whereas in SHR or in the early phase of diabetes, nNOS is increased in macula densa along with NADPH oxidase, which limits NO bioavailability. Renal damage induced by hypertension, diabetes, and hyperlipidemia could be prevented by enhancement of nNOS in macula densa with ACEI, dipyridamole, α₁-receptor blocker, a low-salt diet, or sodium bicarbonate. Sodium bicarbonate is a safe and clinically available enhancer of nNOS in macula densa that increases glomerular blood flow and prevents the reduction of GFR in radiocontrast nephropathy and chronic renal failure. In conclusion, the enhancement of nNOS in the macula densa can be a promising strategy to prevent reduction of renal function.     

Concerted actions of renal endothelial and macula densa NO systems in the maintenance of extracellular fluid volume

It is now clear that nitric oxide (NO) exerts a substantial influence on renal function and that the kidney has a high capacity to produce NO. However, there are at least two different NO systems in the kidney. The interplay between NO generated by the endothelium and by the macula densa is considered in this review. It seems that endothelial NO increases in response to an increase in perfusion pressure and an increase in distal delivery, whereas macula densa NO decreases upon a sustained increase in distal delivery. Furthermore, evidence is accumulating that macula densa NO may well mediate renin release. Though seemingly in contrast, both the response of the endothelial NO and of the macula densa NO system seem appropriate to restore a perturbation of fluid balance. The function of the tubuloglomerular feedback (TGF) mechanism is likely to be influenced by both sources of NO, because of the close proximity of these NO producing cells to the vascular smooth muscle cells of the afferent arteriole. The endothelial NO system seems to be responsible for short-term, dampening actions to increased afferent arteriolar tone elicited by activation of the TGF system. The macula densa NO system, on the other hand, is probably adapting TGF responses to sustained increases in distal delivery. The analysis presented in this paper is an attempt to integrate the function of the two NO systems into physiological regulation. The exact role of the medullary NOS enzymes remains to be further elucidated.     

The juxtaglomerular apparatus in the normal rat kidney

Summary Fifty Juxtaglomerular apparatuses (JGA) from 6 normal rats of two different strains (BD9 and Sprague-Dawley) were studied with serial section technique after vascular perfusion with 1% Glutaraldehyde and embedding in Plexiglass.The macula densa basal area and the contact area between macula densa and the Goormaghtigh cell field were significantly greater in the BD9 rats than in the Sprague-Dawley rats, The contact area between the efferent arteriole and the Goormaghtigh cell field was greater in the Sprague-Dawley than in the BD9 rats. The contact area between the afferent arteriole and the Goormaghtigh cell field was equal in both strains of rat.Significant correlation was found in both strains between the size of the macula densa basal area and its contact area with the Goormaghtigh cells. Similarly there was a significant correlation of the area of contact between the Goormaghtigh cells and the macula densa on the one side and with the afferent arteriole on the other. No correlation was found with the efferent arteriole.Direct contact between macula densa and the arterioles was not present in all Juxtaglomerular apparatuses. It occurred in the BD9 rats in 92% on the afferent and in 52% on the efferent side. In the Sprague-Dawley rats direct contact between macula densa and the arterioles occurred in 59% with the afferent and 72% with the efferent arteriole.Epithelioid cells were found in the preglomerular segment of the afferent arterioles. They replaced the smooth muscle cells in the whole thickness of the media.The results point to the Goormaghtigh cells as the morphological link between the tubular and vascular parts of the Juxtaglomerular apparatus.Supported by the German Research Foundation     

Renal autoregulation in P2X1 knockout mice

Autoregulation of renal blood flow is an established physiological phenomenon, however the signalling mechanisms involved remain elusive. Autoregulatory adjustments in preglomerular resistance involve myogenic and tubuloglomerular feedback (TGF) influences. While there is general agreement on the participation of these two regulatory pathways, the signalling molecules and effector mechanisms have not been identified. Currently, there are two major hypotheses being considered to explain the mechanism by which TGF signals are transmitted from the macula densa to the afferent arteriole. The adenosine hypothesis proposes that the released adenosine triphosphate (ATP) is hydrolysed to adenosine and this product stimulates preglomerular vasoconstriction by activation of A(1) receptors on the afferent arteriole. Alternatively, the P2 receptor hypothesis postulates that ATP released from the macula densa directly stimulates afferent arteriolar vasoconstriction by activation of ATP-sensitive P2X(1) receptors. This hypothesis has emerged from the realization that P2X(1) receptors are heavily expressed along the preglomerular vasculature. Inactivation of P2X(1) receptors impairs autoregulatory responses while afferent arteriolar responses to A(1) adenosine receptor activation are retained. Autoregulatory behaviour is markedly attenuated in mice lacking P2X(1) receptors but responses to adenosine A(1) receptor activation remain intact. More recent experiments suggest that P2X(1) receptors play an essential role in TGF-dependent vasoconstriction of the afferent arteriole. Interruption of TGF-dependent influences on afferent arteriolar diameter, by papillectomy or furosemide treatment, significantly attenuated pressure-mediated afferent arteriolar vasoconstriction in wild-type mice but had no effect on the response in P2X(1) knockout mice. Collectively, these observations support an essential role for P2X(1) receptors in TGF-mediated afferent arteriolar vasoconstriction.     

The structure of the juxtaglomerular apparatus in Addison's disease,Bartter's syndrome,and in Conn's syndrome

Summary Continuing and supplementing previous morphometric studies on the Juxtaglomerular apparatus (JGA) of normal kidneys we have now investigated semi-thin serial sections of each 10 hyperplastic and hypertrophied JGAs in Addison's disease and in Bartter's syndrome, as well as 8 atrophic JGAs in Conn's syndrome. With the exception of Bartter's syndrome, where in only two out of ten JGAs the efferent arteriole, and in none of them the afferent arteriole touches immediately the macula densa, there is an almost regular direct contact between the hilar arterioles and the macula densa like in normal kidneys. The Goormaghtigh cell field invariably touches the macula densa. In Bartter's syndrome, but not in Addison's disease, a considerable enlargement of the macula densa was measured, associated with an exceptional enlargement of the Goormaghtigh cell field. In all cases examined here about 40–60% of the basal area of the macula densa do not have any direct contact with other structures forming the JGA.Supported by the Deutsche Forschungsgemeinschaft.We thank the colleagues of the Institute of Medical Biometry, University of Tübingen, (head: Prof. Dr. M.-P. Geppert) for making all statistical analyses.     

Constitutive nitric oxide synthesis in the kidney--functions at the juxtaglomerular apparatus

Tubulo-vascular information transfer at the renal juxtaglomerular apparatus (JGA) serves to adjust the biosynthesis and release of renin, the key enzyme of the renin angiotensin system, and to regulate glomerular arteriolar muscle tone. The macula densa serves as a sensor of tubular NaCl. Concentration-dependent salt uptake through the Na-K-2Cl cotransporter located in the apical membrane of macula densa cells triggers a signal transduction cascade that involves the synthesis of nitric oxide (NO) through a type 1 NO synthase (NOS1) which is described with respect to its complex mRNA structure and regulatory aspects. The anatomical and functional targets of the NO-soluble guanylyl cyclase-cGMP pathway at the JGA are reviewed.     

Mechanisms for macula densa cell release of renin

The juxtaglomerular apparatus in the kidney is important in controlling extracellular fluid volume and renin release. The fluid load to the distal tubule is first sensed at the macula densa site via the entry of NaCl, through a Na, K, 2Cl co-transport mechanism. The next step is unclear, but there is recent evidence of an increased macula densa cell calcium concentration with a reduction in fluid load to the macula densa. An increase in macula densa cell calcium could activate phospholipase A2 to release arachidonic acid, the rate-limiting step in the formation of prostaglandins. Recent evidence suggests that the prostaglandin formed is PGE2, a potent stimulator for renin release. Recent evidence has also shown that adenosine has an important function in the juxtaglomerular apparatus. It stimulates calcium release in afferent arteriolar smooth muscle cells, leading to contraction of the afferent arteriole as part of the tubuloglomerular feedback mechanism, and inhibits renin release. Thus, renin release from the afferent arteriole is mediated partly through formation of PGE2, and partly through the reduction of adenosine formation that inhibits renin production.     

Constitutive nitric oxide synthesis in the kidney – functions at the juxtaglomerular apparatus

Tubulo‐vascular information transfer at the renal juxtaglomerular apparatus (JGA) serves to adjust the biosynthesis and release of renin, the key enzyme of the renin angiotensin system, and to regulate glomerular arteriolar muscle tone. The macula densa serves as a sensor of tubular NaCl. Concentration‐dependent salt uptake through the Na‐K‐2Cl cotransporter located in the apical membrane of macula densa cells triggers a signal transduction cascade that involves the synthesis of nitric oxide (NO) through a type 1 NO synthase (NOS1) which is described with respect to its complex mRNA structure and regulatory aspects. The anatomical and functional targets of the NO‐soluble guanylyl cyclase‐cGMP pathway at the JGA are reviewed.     

Tubule-tubule and tubule-arteriole contacts in rat kidney distal nephrons. A morphologic study based on computer-assisted three-dimensional reconstructions.

BACKGROUND: Functional investigations of the tubulo-glomerular feedback mechanism have indicated the existence of a contact between the distal nephron and the macula densa region. The structural justification of such a contact is investigated. EXPERIMENTAL DESIGN: Tubule-tubule and tubule-arteriole contacts were investigated in distal nephrons from normal rat kidneys. Computer-assisted three-dimensional reconstructions of distal nephrons were made from serial sections of renal cortical tissue and selected sections were examined by electron microscopy. RESULTS: In 14 of 15 reconstructed nephrons, the distal convoluted tubule or the connecting tubule approached the macula densa region. A wall-to-wall contact between two tubules corresponding to a three-dimensional distance below 28 microns between the axes of the two tubules was found in only five of the reconstructed tubules. The distal nephron contacts to afferent and efferent arterioles of the same nephron were also examined. The efferent arteriole revealed no consistent contacts but the afferent arteriole contacted the distal convoluted tubule/connecting tubules consistently in all 10 of the superficial nephrons and in 3 of 5 midcortical nephrons. Electron microscopy confirmed a close contact between the distal tubule and the afferent arteriole in superficial nephrons and small nerves were often found at or near the site of contact, but the morphology at the site of contact was not unique. The arteriole contacts were made with late distal convoluted tubules, connecting tubules, or cortical collecting ducts. CONCLUSIONS: In conclusion, the present study shows that tubule-tubule contacts are inconsistent between the macula densa region and the distal nephron but that the tubule-afferent arteriole contact is consistent and close in superficial nephrons. This morphology is compatible with the existence of a feedback mechanism between the superficial distal nephron and the afferent arteriole, apart from the one located at the juxtaglomerular apparatus.     

Resetting of tubuloglomerular feedback by interrupting early distal flow

Cell–cell contact between the macula densa and the glomerular arterioles is thought to provide the information pathway for the tubuloglomerular feedback (TGF) mechanism. When concentrations of sodium and chloride in the macula densa segment are increased, a signal is transmitted through the extraglomerular mesangium to contract the afferent arteriole. In addition, some observers have described a second region of contact between a later part of the distal tubule and the afferent arteriole of the same nephron. In this region the connecting tubule (CNT), and sometimes nerves that make contact with the cells of this CNT, were found. This arrangement gives another potential tubular segment, besides the macula densa plaque, in which the composition of tubular fluid may regulate glomerular dynamics. The present study was designed to investigate whether interrupting flow in the distal tubule downstream from the macula densa would influence the TGF mechanism. TGF was examined in rats by orthograde microperfusion, before and after blockade of the distal nephron with castor oil. Two variables were measured: maximum decrease in stop-flow pressure (ΔP_sf), and perfusion rate which elicits half-maximal decrease in ΔP_af (V_1/2). The fluid arriving at the blocking point was collected into a micro-pipette. The results show a significant increase in V_1/2 from 19 to 25 nl min^-1after 30 min of blockade. In conclusion the results support a role of the distal nephron in the control of the TGF mechanism.     

Conducted vasomotor responses in arterioles: characteristics,mechanisms and physiological significance

Micropipette application of certain vasoconstrictor or -dilator substances onto the surface of arterioles induces both a local vasomotor response and a response which is propagated up- and downstream along the vessel, a so-called conducted vasomotor response. In some vascular beds conducted vasoconstrictor and dilator responses are detectable more than a millimetre from the site of agonist delivery. While agonists such as acetylcholine, noradrenaline, and KCl almost invariably give rise to conducted vasomotor responses others, such as sodium nitroprusside or vasopressin, do not. Conducted vasomotor responses in arterioles appear to rely on passive electrotonic spread of the change in membrane potential induced by the agonist at the tip of the pipette. Presumably the current spreads up- and downstream along the arteriolar wall through endothelial or smooth muscle cell gap junctions. Whether the electrical signal is conducted primarily through the endothelial or the smooth muscle cell layer or both is currently not known, but it may depend on the agonist used. Experiments have suggested that conducted vasodilation in skeletal muscle feed arterioles plays an important role in the development of functional hyperaemia at the onset of exercise. In the kidney, conducted vasoconstriction is believed to be responsible for the upstream contraction of the afferent arteriole and interlobular artery known to occur in response to activation of the macula densa. Therefore conducted vasoconstriction could be important for the tubuloglomerular feedback mechanism. Finally, experimental studies have shown that conduction of vasomotor responses in arterioles may be altered in pathological conditions associated with microvascular dysfunction such as arterial hypertension and sepsis.     

Conducted vasomotor responses in arterioles: characteristics, mechanisms and physiological significance.

Micropipette application of certain vasoconstrictor or -dilator substances onto the surface of arterioles induces both a local vasomotor response and a response which is propagated up- and downstream along the vessel, a so-called conducted vasomotor response. In some vascular beds conducted vasoconstrictor and dilator responses are detectable more than a millimetre from the site of agonist delivery. While agonists such as acetylcholine, noradrenaline, and KCl almost invariably give rise to conducted vasomotor responses others, such as sodium nitroprusside or vasopressin, do not. Conducted vasomotor responses in arterioles appear to rely on passive electrotonic spread of the change in membrane potential induced by the agonist at the tip of the pipette. Presumably the current spreads up- and downstream along the arteriolar wall through endothelial or smooth muscle cell gap junctions. Whether the electrical signal is conducted primarily through the endothelial or the smooth muscle cell layer or both is currently not known, but it may depend on the agonist used. Experiments have suggested that conducted vasodilation in skeletal muscle feed arterioles plays an important role in the development of functional hyperaemia at the onset of exercise. In the kidney, conducted vasoconstriction is believed to be responsible for the upstream contraction of the afferent arteriole and interlobular artery known to occur in response to activation of the macula densa. Therefore conducted vasoconstriction could be important for the tubuloglomerular feedback mechanism. Finally, experimental studies have shown that conduction of vasomotor responses in arterioles may be altered in pathological conditions associated with microvascular dysfunction such as arterial hypertension and sepsis.     

Long-term studies of the juxtaglomerular apparatus in young microalbuminuric type 1 diabetic patients

AIM: To determine the long-term changes of the juxtaglomerular apparatus in incipient diabetic nephropathy. METHODS: Three renal needle biopsies were performed on 15 young type I diabetic patients with microalbuminuria; at baseline and after an average of 2.4 and 8.2 years. Using light microscopy, 1 microm serial sections of the plastic-embedded biopsies were investigated and volumes of the juxtaglomerular apparatus and glomerulus and areas of the macula densa and lumina of the afferent and efferent arterioles were measured. RESULTS: From baseline to second follow-up there was a significant decrease in JGA relative to glomerular volume. There was an increase in luminal area of the efferent arteriole which was paralleled by (non-significant) changes in the afferent arteriole. CONCLUSION: Over a period of 8.2 years JGA size remained stable, but decreased relative to glomerular size. Also, an increase in luminal area was noted in efferent arterioles. This may be due to increased single nephron blood flow secondary to nephron loss.     

Interaction between nitric oxide and oxygen radicals in regulation of tubuloglomerular feedback

NADPH oxidase, nitric oxide synthase (NOS) and cyclooxygenase are oxidases that are expressed in the juxtaglomerular apparatus (JGA) or blood vessels and can generate oxygen radicals (O-2) during partial reduction of molecular oxygen. O-2 interacts rapidly and irreversibly with nitric oxide (NO) to yield peroxynitrite (ONOO-), thereby restricting the half-life, diffusion distance and bioactivity of NO in tissues. NO generated by a neuronal (n) NOS isoform that is heavily expressed in macula densa (MD) cells, is generated during NaCl reabsorption at the MD and blunts the expression of the tubuloglomerular feedback (TGF) response. Therefore, we tested the hypothesis that O-2 formed in the JGA of the normal rat limits NO signalling. Tempol is a membrane-permeable superoxide dismutase (SOD) mimetic. Maximal TGF responses were assessed from the fall in proximal stop flow pressure during orthograde perfusion of artificial tubular fluid (ATF) into the loop of Henle. Microperfusion of tempol (10-4 M) into the efferent arteriole (EA) of Wistar-Kyoto rats blunted maximal TGF response (8. 2 +/- 0.4 vs. 6.4 +/- 0.4 mmHg; n=8; P < 0.05). Graded doses of the NO donor compound, S-nitroso-acetylpenicillamine (SNAP; 10-7-10-4 M) microperfused into the lumen of the MD produces graded buffering of TGF. During EA microperfusion of tempol, responses to luminal SNAP at 10-6 M and greater were enhanced significantly (P < 0.05 or <0. 01). In conclusion, O-2 generated in the JGA can be metabolized by a membrane-permeable SOD mimetic. O-2 enhances the basal TGF response and limits NO signalling from the macula densa. Therefore, O-2 and NO interact in the JGA to modulate the TGF response.     

Renal NO production and the development of hypertension

The juxtaglomerular apparatus (JGA) has the very important functions of detecting the fluid flow rate to the distal tubule and thus controlling the glomerular filtration rate (GFR) (tubuloglomerular feedback mechanism [TGF]) and renin release from the afferent arteriole. In studies of the TGF it has been evident that the sensitivity of this mechanism can be reset. Volume expansion will reset it to a low sensitivity leading to a high GFR and urine excretion rate, while dehydration will sensitize the TGF mechanism, giving rise to a low GFR and low urine excretion rate. Furthermore, we have found that in animals that spontaneously develop hypertension there is initially a sensitization of the TGF, leading to a reduced GFR and urine excretion rate, with fluid volume retention in the body and a consequent rise in blood pressure. When the pressure is raised, the TGF characteristics are normalized. In the macula densa (MD) cells in the JGA, there is a large production of NO from neuronal NOS. This production continuously reduces TGF sensitivity and is apparently impaired in animals that spontaneously develop hypertension. When we added an nNOS inhibitor to the drinking water for several weeks while measuring blood pressure, we found an increase in blood pressure after 3-4 weeks of treatment. This effect was abolished by a high salt diet. From these investigations, it also appeared as if nNOS-derived NO inhibited renin release. Experiments have also indicated that NO may resensitize inhibited G-protein coupled purinergic receptors.     

Current mechanisms of macula densa cell signalling

Macula densa cells couple renal haemodynamics, glomerular filtration and renin release with tubular fluid salt and water reabsorption. These cells detect changes in tubular fluid composition through a complex of intracellular signalling events that are mediated by membrane transport pathways. Increases in luminal fluid sodium chloride concentration result in alterations in cell sodium chloride concentration, cytosolic calcium, cell pH, basolateral membrane depolarization and cell volume. Macula densa signalling then involves the production and release of specific paracrine signalling molecules at their basolateral membrane. Upon moderate increases in luminal sodium chloride concentration macula densa cells release increasing amounts of ATP and decreasing amounts of prostaglandin E(2), thereby increasing afferent arteriolar tone and decreasing the release of renin from granular cells. On the other hand, further increases in luminal concentration stimulate the release of nitric oxide, which serve to prevent excessive tubuloglomerular feedback vasoconstriction. Paracrine signalling by the macula densa cells therefore controls juxtaglomerular function, renal vascular resistance and participates in the regulation of renin release.     

Cell calcium concentration in glomerular afferent and efferent arterioles under the action of noradrenaline and angiotensin II

The glomerular arterioles in the juxtaglomerular apparatus seem to function as effectors of the tubuloglomerular feedback mechanism. In this mechanism increased delivery of fluid to the distal nephron activates the macula densa cells through transport via an Na-2C1-K cotransporter. This activation may lead to vasoconstriction of the afferent arteriole. Furthermore, vasoactive substances seem to affect both afferent and efferent arterioles. There are morphological differences along the afferent arteriole, some parts containing epithelioid cells with renin granules and others regular smooth muscle cells. The aim of the present experiments was to determine whether noradrenaline (10?⁶ M) and angiotensin II (10?⁶ M) had differential effects on the cell calcium concentration [Ca²⁺]j and on contraction in isolated perfused afferent and efferent arterioles and in the mesangial region. [Ca²⁺], was measured with fura-2, an intensified videocamera and a digital imaging system. From the proximal to the distal part of the arteriole [Ca²⁺], increased from about 100 to 250 nM. A [Ca²⁺], increase and a contraction were caused by noradrenaline alone in the proximal part of the afferent arteriole and by angiotensin II alone in the distal part of this arteriole. In the mesangial region there was a high basal [Ca²⁺], but no response to the vasoactive substances. In the efferent arteriole, application of both noradrenaline and angiotensin II led to an increase in [Ca²⁺]₁ and a contraction. The present experiments indicate that the two vasoactive substances tested act in a similar fashion along the whole length of the efferent arteriole, while in the afferent arteriole their actions are not equally distributed.     

Interactions of the renin-angiotensin system and neuronal nitric oxide synthase in regulation of cyclooxygenase-2 in the macula densa

Cyclooxygenase-2 (COX-2) expression in rat kidney is localized to the macula densa and the immediately proximal cTALH and increases after salt restriction. Either ACE inhibitors or AT1 receptor blockers increase COX-2 expression in both control and salt-restricted animals, suggesting that the RAS activation feedback inhibits renal cortical COX-2 expression. To determine whether increased COX-2 expression in response to ACE inhibition mediated increases in renin production, rats were treated with Captopril for 1 week with or without the specific COX-2 inhibitor, SC58236. Plasma renin activity increased significantly in the Captopril group. This increase was partially reversed by simultaneous treatment with SC58236. Kidney renin activity also increased in the Captopril group compared with control, which was also significantly inhibited by SC58236 treatment. Because of the localization of bNOS to MD and surrounding cTALH, the current study investigated the role of NO in the regulation of COX-2 expression. Rats were fed a normal diet, low salt diet or low salt diet combined with captopril and half of them were treated with the neuronal NOS inhibitor, 7-NI, and half with vehicle. After 7 days, mRNA was extracted and the microsome proteins purified from renal cortex. COX-2 mRNA expression was measured by Northern-blot and normalized with GAPDH. 7-NI treatment decreased COX-2 mRNA and immunoreactive COX-2 expression in each group. In summary, these studies indicate that COX-2 from macula densa/cTALH is a regulator of renin production and release. Angiotensin II may be a negative regulator of cTALH/macula densa COX-2 expression, and NO may mediate increased renal cortical COX-2 expression seen in volume depletion. These studies suggest important interactions between the NO and COX-2 systems in the regulation of arteriolar tone and the renin-angiotensin system by the macula densa.     

Structure of renal afferent arterioles in the pathogenesis of hypertension

Renal vascular resistance is increased in essential hypertension, as in genetic models of hypertension. Here we review the evidence that this is at least in part due to structural changes in the afferent arterioles. Rat studies show that the renal afferent arteriole is structurally narrowed in young and adult spontaneously hypertensive rats (SHR). Furthermore, in the second generation of crossbred SHRs/normotensive rats (SHR/WKY F(2)-hybrids), a narrowed afferent arteriole lumen diameter at 7 weeks is a predictor of later development of high blood pressure. The reduced lumen diameter of resistance vessels is accompanied by a decrease in media cross-sectional area in SHR and could therefore be due to inhibited growth. Evidence from a primate model of hypertension has shown a negative correlation between left ventricular hypertrophy and afferent arteriole diameter, but apparently no relation to blood pressure. In SHR, the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors is mediated through renal vascular mechanisms, while ACE inhibitors (like AT(1) antagonists) have a more persistent effect on blood pressure after treatment withdrawal compared with other antihypertensive drugs. Taken together, the evidence suggests that structural narrowing of the renal afferent arteriole could be an important link in the pathogenesis of primary hypertension, at least in the SHR.