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 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.

Morphological changes of the arterial systems in the kidney under prolonged continuous flow left heart bypass.

We investigated morphological changes of the arterial systems in the kidneys under prolonged continuous flow left heart bypass. Twelve goats were subjected to 2 weeks of pulsatile left heart bypass followed by 4 weeks of continuous flow left heart bypass (group CF). After autopsy, the kidneys underwent pathological evaluation. Six normal healthy goats were used as controls. The media of the afferent arterioles of group CF were frequently thickened by an increase in the number of the mature smooth muscle cells (SMCs). The juxtaglomerular areas (JGA) were expanded because of an increase in the number and size of SMCs and/or SMC-like cells. Furthermore, the percentage of anti-proliferating cell nuclear antigen antibody-positive cells in the JGA of group CF (9.9 +/- 1.9%) was significantly higher (p = 0.025) than that of the control group (4.6 +/- 3.4%), indicating active proliferation in group CF. We concluded that prolonged continuous flow left heart bypass causes proliferation of SMCs and/or SMC-like cells in the afferent arterioles and their perivascular tissue.

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.

TGF-beta1-induced glomerular disorder is associated with impaired concentrating ability mimicking primary glomerular disease with renal failure in man.

Transforming growth factor-beta1 (TGF-beta1) may play a major role in the pathogenesis of glomerulopathy and end-stage renal disease (ESRD). The aim of this study was to explore the functional consequences of localized overproduction of TGF-beta1 in relation to glomerular ultrastructure and the composition of the extracellular matrix (ECM) in the inner medulla. We used a transgenic mouse with overexpression of TGF-beta1 targeted to the juxtaglomerular apparatus (JGA) by the Ren-1c promoter. The kidney function was evaluated using urine production and metabolite excretion over a 24-hour period, glomerular filtration rate (GFR), and concentrating ability. The glomerular structure was analyzed in terms of volume, ie, the volume of the mesangium per glomerulus (Vv[mes/glom]) and the volume of the matrix per glomerulus (Vv[matrix/glom]), ECM per glomerulus, the area of the filtration surface, and the thickness of the peripheral basement membrane (PBM). Immunohistochemistry or in situ hybridization was used to examine the expression of aquaporin 2 (AQP2), plasminogen activator inhibitor-1 (PAI-1), and the composition of the ECM in the inner medulla. The mice exhibited polyuria, reduced concentrating ability, decreased GFR, and albuminuria paralleled by increased glomerular volume, with increased volume of ECM, decreased filtration surface, and thickening of the PBM being detectable between 1 and 2 months of age. The deposition of glomerular ECM was accompanied by increased levels of PAI-1. As estimated by excretion of Clara cell protein-1 (CC16) and lysozyme, tubular damage occurred only in older mice. Collagen Type I was deposited in the inner medulla in the presence of normal AQP2-expression in the collecting ducts. This study reached the following conclusions: (a) TGF-beta1 reduces the GFR and the glomerular filtration surface, (b) TGF-beta1 induces albuminuria in association with widening of the PBM, (c) expansion of the mesangial volume seems to precede the widening of the PBM, (d) TGF-beta1-induced accumulation of glomerular ECM is partly explained by increased PAI-1 expression, (e) Decreased concentrating ability and polyuria caused by accumulation of ECM in the inner medulla may be an early marker of glomerular diseases associated with increased expression of TGF-beta1 in man.

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.

Kidney and hypertension: role of the juxtaglomerular apparatus.

The kidney plays an important role in the pathophysiology of hypertension. Recent studies suggest that glomerular hemodynamics may be critically involved not only in the pathogenesis of hypertension but also in the mode of progression of renal dysfunction. The juxtaglomerular apparatus (JGA), consisting of the glomerular afferent and efferent arterioles and the specialized tubular epithelial cells called the macula densa, plays a central role in the regulation of glomerular hemodynamics and renin release. This article reviews the mechanism by which the JGA controls renin release and glomerular hemodynamics as well as its relevance in the pathogenesis, pathophysiology and treatment of hypertension.

Functional and morphometric evaluation of offspring kidney after intrauterine undernutrition.

Pregnant rats were subjected to 50% food restriction during the first or the second half of pregnancy, or throughout pregnancy. The effects of intrauterine food restriction, on kidney function and morphometry were studied in newborn and adult (3 months) offspring. No differences in glomerular diameter were observed in newborn restricted rats compared with controls. The number of glomeruli was significantly lower both in newborn and 3-month-old restricted rats. However, glomerular diameter was increased in 3-month-old rats, which suggests that hypertrophic stimuli were present. The medulla/cortex ratio increased in adult rats submitted to food restriction during pregnancy, a finding that agrees with the preserved sodium and acid excretion, and the normal osmolar and free water clearance observed in these groups. These results show that the reduction in glomerular number is still present 3 months after birth in the progeny of mothers submitted to severe food restriction during pregnancy, suggesting impairment of glomerulogenesis even after birth. Intra utero undernutrition can be regarded as an experimental model of glomerular hypertrophy.

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.

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.

[Pathophysiology of the renin-angiotensin system]. / Pathophysiologie des Renin-Angiotensinsystems.

The renin angiotensin system is an important system for the regulation of blood pressure and salt and water homeostasis. As a pathogenetic factor it is involved in the development of several forms of renal hypertension and, furthermore, it participates in the pathogenesis of primary and secondary hypertension. The regulation of the activity of the system is under the control of neuronal and hormonal mechanisms and depends on blood pressure and plasma concentrations of sodium chloride. With the development of converting enzyme inhibitors and their vasodilator, diuretic and sympatholytic actions a new important antihypertensive principle for lowering blood pressure was found. In this context also local renin angiotensin systems which have been described for several tissues have to be discussed as a possible target of action for converting enzyme inhibitors.

[Functional morphology of the adrenal cortex and incretory kidney structures in the salt-losing form of adrenogenital syndrome in children]. / Funktsional'naia morfologiia kory nadpochechnikov i inkretornykh struktur pochek pri sol'teriaiushchei forme adrenogenital'nogo sindroma u detei.

The adrenals and kidney incretory structures (the juxtaglomerular apparatuses and renomedullary interstitial cells) were studied in 12 cases of a desalinization form of the adrenogenital syndrome in children who died at the age of 1-6 mos of acute water-electrolytic disturbances in order to assess function of the structures involved in the regulation of the water-salt equilibrium. The adrenals and kidneys from 7 children of the same age who died of mechanical asphyxia, were taken as controls. The depth of adrenocortical zones, volumes of nuclei and nucleoli in different cortical zones were determined; the juxtaglomerular index, cell count (including vacuolized cells), the area of the juxtaglomerular apparatus and mesangium were determined in the juxtaglomerular apparatus. The amount of cell lipid granules (the interstitial-cellular index), the mean granule volume and the total granule volume were counted in renomedullary interstitial cells. The results were statistically processed, and a paired correlation analysis of all the studied parameters was performed. In the desalinization form of the adrenogenital syndrome morphometric investigation of the glomerular and fascicular zones revealed compensatory processes, not of hyperplastic nature but mainly of hypertrophic nature; morphological and morphometric characteristics of the kidney incretory structures indicated tension of the renin-angiotensin system and probably a decrease in prostaglandin synthesis in salt and water loss. In the control group parameters of structures related to the regulation of the water-salt equilibrium, especially in the adrenal cortex, showed good correlation. In the desalinization form of the adrenogenital syndrome some other relationships between these structures developed.

The changes in active and inactive renin induced by various maneuvers in hypertensive patients.

The changes in active and inactive renin after captopril (n = 29) or furosemide administration (n = 10) were studied in hypertensive patients. Furthermore, after percutaneous transluminal angioplasty (PTA) in 3 cases of renovascular hypertension (RVH), and after nephrectomy in a case of juxtaglomerular cell tumor, the time course of the changes in these two types of renin was investigated. Inactive renin was activated by trypsin treatment. Plasma renin concentration was measured by using an excess of sheep substrate. In patients with essential hypertension or primary aldosteronism, inactive renin was unchanged, irrespective of response in active renin, after the administration of captopril and furosemide. In patients with RVH, inactive renin was markedly decreased by furosemide but unchanged by captopril, in spite of significant increase in active renin. After PTA and nephrectomy, inactive renin decreased slower than active renin. These data support the idea that in patients with RVH, the increase in active renin by furosemide is at least partly due to the activation of inactive renin. It is also suggested that the increase in active renin by captopril is mainly due to the promoted release of active renin from the kidney. Furthermore, it seems likely that the metabolic clearance of inactive renin is slower than that in active renin.