[The cortical collecting duct plays a pivotal role in the kidney's local renin-angiotensin system]. / A gyujtocsatorna meghatározó szerepe a vese lokális renin-angiotenzin rendszerében.

The renin-angiotensin system is one of the most important hormone systems in the body, and the regulations as well as the role in the juxtaglomerular apparatus are well known. The present review focuses on renin secretion in a recently described localization, the cortical collecting duct. The authors display it in parallel of the copying strategy of an adult and a developing kidney. Furthermore, based on different animal studies it highlights the local role of renin released from the collecting duct. In chronic angiotensin II-infused, 2-kidney, 1-clip hypertensive model as well as in diabetic rats the major source of (pro)renin is indeed the collecting duct. In this localization this hormone can reach both the systemic circulation and the interstitial renin-angiotensin system components including the newly described (pro)renin receptor, by which (pro)renin is able to locally activate pro-fibrotic intracellular signal pathways. Consequently, one can postulate that in the future renin may serve either as a new therapeutic target in nephropathy associated with both hypertension and diabetes or as an early diagnostic marker in chronic diseases leading to nephropathy.

Disruption of the dopamine D3 receptor gene produces renin-dependent hypertension.

Since dopamine receptors are important in the regulation of renal and cardiovascular function, we studied the cardiovascular consequences of the disruption of the D3 receptor, a member of the family of D2-like receptors, expressed in renal proximal tubules and juxtaglomerular cells. Systolic and diastolic blood pressures were higher (approximately 20 mmHg) in heterozygous and homozygous than in wild-type mice. An acute saline load increased urine flow rate and sodium excretion to a similar extent in wild-type and heterozygous mice but the increase was attenuated in homozygous mice. Renal renin activity was much greater in homozygous than in wild-type mice; values for heterozygous mice were intermediate. Blockade of angiotensin II subtype-1 receptors decreased systolic blood pressure for a longer duration in mutant than in wild-type mice. Thus, disruption of the D3 receptor increases renal renin production and produces renal sodium retention and renin-dependent hypertension.

Role of the Primary Cilia on the Macula Densa and Thick Ascending Limbs in Regulation of Sodium Excretion and Hemodynamics.

We investigated the significance of the primary cilia on the macula densa and thick ascending limb (TAL) in regulation of renal hemodynamics, sodium excretion, and blood pressure in this study. A tissue-specific primary cilia knock-out (KO) mouse line was generated by crossing NKCC2-Cre mice with IFT88-Δ/flox mice (NKCC2CRE; IFT88Δ/flox), in which the primary cilia were deleted from the macula densa and TAL. NO generation was measured with a fluorescent dye (4,5-diaminofluorescein diacetate) in isolated perfused juxtaglomerular apparatus. Deletion of the cilia reduced NO production by 56% and 42% in the macula densa and TAL, respectively. NO generation by the macula densa was inhibited by both a nonselective and a selective nitric oxide synthesis inhibitors, whereas TAL-produced NO was inhibited by a nonselective and not by a selective NO synthesis 1 inhibitor. The tubuloglomerular feedback response was enhanced in the KO mice both in vitro measured with isolated perfused juxtaglomerular apparatuses and in vivo measured with micropuncture. In response to an acute volume expansion, the KO mice exhibited limited glomerular filtration rate elevation and impaired sodium excretion compared with the wild-type mice. The mean arterial pressure measured with telemetry was the same for wild-type and KO mice fed a normal salt diet. After a high salt diet, the mean arterial pressure increased by 17.4±1.6 mm Hg in the KO mice. On the basis of these findings, we concluded that the primary cilia on the macula densa and TAL play an essential role in the control of sodium excretion and blood pressure.

The pathophysiology of renovascular hypertension.

Renovascular hypertension, comprising a small percentage of the total hypertensive population, stands out as remarkably important, being the most common cause of surgically correctable hypertension. Its precise diagnosis can be accomplished by judicious application of recently available sophisticated laboratory methods and correct prediction of curability is now possible. Careful selection of cases among the vast numbers of hypertensives by routine screening procedures is essential. The selected few deserve more complete studies including bilateral renal vein renin measurements. Rapid sequence pyelography, split function studies, radioisotope renorgram, and renal arteriography accurately define the presence of a significant structural abnormality involving the renal circulation on either side. Significant bilateral renal vein plasma renin differential, done under appropriate conditions of volume depletion and upright posture, in the absence of interference by concurrent antihypertensive drug therapy, establishes a causal relationship between the structural abnormality and the high blood pressure. A thorough knowledge of the normal physiology of the renin-angiotensin-aldosterone system and its inappropriate response in renovascular hypertension and other related clinical conditions is clearly necessary if one is to plan diagnostic studies intelligently and interpret the results correctly.

Possible role of juxtaglomerular apparatus in low cardiac output syndrome and multiple organ failure: modulation by high sodium load.

Sympathetic overdrive in acute low cardiac output syndrome, diverts blood from cutaneous and visceral circulation centripetally. Microcirculation in general, and renal circulation in particular, deteriorates during these circulatory adjustments leading to multi-organ failure (MOF). Decreased afferent glomerular arteriolar blood flow, increased renal sympathetic nerve discharge and a resultant decreased sodium chloride delivery around macula densa stimulates the Juxta-glomerular apparatus (JGA) and triggers renin-angiotensin-aldosterone mechanism. This, along with increased ADH production results in a state of vasoconstriction, increased after-load, and continued fluid retention, further compromising the visceral microcirculation. Initially the fluid retention under the effect of aldosterone and ADH is iso-osmotic, but later under inappropriate ADH action more water than salt is retained, as evidenced by the presence of hyponatraemia and 'water-logging' in the endstage of this condition.The author hypothesizes that: although physiological, the persistent stimulation of the JGA during the low cardiac output state plays an important role in perpetuating a negative cardiovascular vicious cycle and further aggravating it into MOF. Furthermore, by infusing hypertonic saline and hence increasing the sodium chloride delivery to the distal tubules and the macula densa, the JGA could be inhibited. This strategy should work like angiotensin-converting-enzyme-inhibitor drugs in chronic cardiac failure, except by acting at the root cause and inhibiting Renin production at its source. It should further help by stimulating atrial natriuretic peptide secretion.

The renin-angiotensin system in cats with chronic renal failure.

The kidneys of eight male and two female cats with subacute (clinical illness 1-3 months) to chronic (clinical illness > 3 months) renal failure were examined histopathologically, electron microscopically and immunohistochemically. Semiquantitative morphometric data, obtained by measurement of the reninpositive portion of the afferent arteriole (RPP) and evaluation of the juxtaglomerular index (JGI), were compared with data from three healthy control cats. On the basis of the morphometric data, the animals with renal failure could be classified in three groups showing either a stimulated (group A), an unaltered (group B) or an inhibited (group C) renin-angiotensin system. In the three group A cats the JGI and RPP were increased (45.5 +/- 3.5%; 130 microns); in the four group B cats these values were comparable with those of the controls; in the three group C animals the JGI was decreased but the RPP was unaltered (11.7% +/- 3.2%; 56 microns). The increase in kidney renin in animals affected by chronic renal failure (CRF) may have been due to a volume depletion. Prolonged CRF seemed to result in increasing hypertrophy of renal blood vessels, leading to renal hypoxia and increasing preglomerular resistance. Reduced kidney renin status may have been caused by inhibition of renin synthesis in prolonged CRF as a result of renal ischaemia.

Neurohumoral mechanisms in hypertension.

Neurohumoral mechanisms operating via the catecholamines are discussed in their relationship to such hypertensive diseases as pheochromocytoma and labile and established essential hypertension. 2. In pheochromocytoma, diagnosis depends almost entirely on identification of increased amounts of catecholamine metabolites in the urine. Because of the danger, manipulative or invasive procedures both for diagnosis and during surgery should be kept at a minimum. 3. In established essential hypertension, reactivity to norepinephrine and plasma norepinephrine are increased, whereas norepinephrine uptake and apparent secretion rate are decreased. 4. In labile essential hypertension, reactivity to epinephrine and probably plasma epinephrine are increased and uptake of epinephrine decreased. 5. Labile hypertension with all its characteristics may or may not coexist with established essential hypertension with all its features. 6. The sympathetic nervous system is also involved in other types of hypertensive disease. Many patients with renovascular hypertension as well as with primary and secondary hyperaldosteronism also have essential hypertension. Angiotensin II affects the sympathetic nervous system and the juxtaglomerular apparatus appears to be beta adrenergic receptor activated, at least in part.

Arterial hypertension--a disease of the juxtaglomerular apparatus?

From a special strain of genetically hypertensive rats, the Milan hypertensive strain (MHS), arterial hypertension can be transplanted with the kidney to the Milan normotensive strain (MNS). During development of hypertension in MHS rats there was an activation of the tubuloglomerular feedback control that reduced glomerular filtration rate, leading to retention of electrolytes and fluid. This increased extracellular fluid volume reduces feedback sensitivity, but in a fashion that gives rise to chronic extracellular fluid expansion and can thereby raise the blood pressure. In a limited sense, arterial hypertension in these animals exists to prevent the kidney from retaining more extracellular fluid volume. The altered function in the juxtaglomerular apparatus of the MHS rats thus may explain the rise in arterial blood pressure.

Functional interpretation of the kidney juxtaglomerular apparatus using renin immunohistochemistry in Bartter's, pseudo-Bartter's and Conn's syndromes.

A comparative study of renin immunoreactivity in the juxtaglomerular apparatus of the human kidney was performed using the indirect immunoperoxidase method on a random microscopic sections. In renal biopsies taken from a case of Bartter's syndrome and a case of pseudo-Bartter's syndrome, the number of renin-positive juxtaglomerular apparatus (JGA) and the number of renin-positive cells in each JGA were significantly greater than in five renal specimens from control autopsy cases. In Conn's syndrome, none of the glomeruli contained renin-immunoreactive JGA. The number of renin-positive cells/mm2 in the renal cortex in cases of Bartter's and pseudo-Bartter's syndromes were 17.5 and 20.3, respectively, while in the control group, the range was 0.78-1.77 (mean 1.08). Together with other histochemical findings routinely examined in renal specimens, renin immunohistochemistry on random sections may be helpful in diagnostic renal pathology.

[Restructuring of the endocrine function of the kidney in hypertension]. / Perestroika éndokrinnoi funktsii pochek u bol'nykh gipertonicheskoi bolezn'iu.

The author studied the renin-angiotensin, and kallikrein-kinin systems and renal prostaglandins in patients with different stages of hypertension. The activity of plasma renin and the content to PG in the peripheral blood and the blood from the renal veins, PGE2 excretion, PGG2 and kallikrein in the urine have been studied. Overloads have been used, directed at the activation of the sympathetic nervous system. It is concluded that a functional rearrangement of the endocrine renal function exists in patients with the hypertensive disease, which is related to the development of defects in the control of one series of the humoral systems and to the compensatory changes in the others. The increase of extracellular volume is the reason of the functional endocrine changes in the kidney, which is shown by the results of studies after salt overloads.

[State of the sympathetic-adrenal system and renin activity in the blood in children with primary arterial hypertension in the process of beta-blockader treatment]. / Sostoianie simpatiko-adrenalovoi sistemy i aktivnost' renina v krovi u detei s pervichnoi arterial'noi gipertoniei v protsesse lecheniia beta-blokatorami.

The condition of the sympatheticoadrenal system and blood renin activity were studied in healthy children and in children suffering from primary arterial hypertension and treated with beta-blocking agents (Obzidan, Visken). A hypotensive effect was noted in the group of patients suffering from primary arterial hypertension with a high blood renin level and increased excretion of catecholamines in the urine.

[Structural foundation for the functional connections of the endocrine apparatus and nervous system of the kidneys]. / Strukturnoe obosnovanie funktsional'nykh sviazei éndokrinnykh apparatov i nervoi sistemy pochek.

Data from the current literature are used to demonstrate the structural-functional relationship of endocrine and nervous apparatuses of the kidneys which must be taken into consideration in the analysis of clinical manifestations and pathogenesis of many diseases, first of all those of the kidneys. Therefore it is recommended that in examinations of kidney biopsies the state of the endocrine apparatuses and nervous system be evaluated which requires deep kidney biopsy and special methods of morphological analysis.