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This report presents a case of a 16-year-old hypertensive boy who presented to our clinic. Laboratory findings showed severe hypokalemia and markedly increased plasma renin activity. Abdominal ultrasonography and contrast-enhanced computed tomography of the abdomen revealed a well-circumscribed, solid, hypoenhancing cortical lesion (2 cm) in the lower pole of the left kidney. The patient underwent nephron-sparing surgery. Histopathologic examination gave a diagnosis of juxtaglomerular cell tumor. Reninoma is an uncommon cause of hypertension in a young adult and should be included in the differential diagnosis as a potential life-threatening and curable condition. The conservative surgical management is the gold standard for small, circumscribed lesions., (Copyright (c) 2010 S. Karger AG, Basel.)

Recent evidence obtained in rodents indicates that gap junctions in the juxtaglomerular apparatus play an important role in the control of renin-producing cells and in tubuloglomerular signaling. These gap junctions are formed by cell-specific expression patterns of the vascular connexins Cx37, Cx40, Cx43 and Cx45. In order to obtain a first indication if gap junctions might play a similar important functional role in the juxtaglomerular apparatus of human kidneys, this study aimed to characterize the juxtaglomerular localization of Cx40, Cx37, Cx43 and Cx45 in human kidney specimens. We found Cx37, Cx40 and Cx43, but not Cx45 expression in high density in the extraglomerular mesangium. Renin-producing cells displayed strong immunoreactivity for Cx40 and Cx37. Cx37, Cx40 and Cx43 were also seen in the endothelium of arteries/arterioles outside of the glomeruli, whereas Cx45 was located in vascular smooth muscle cells. All four connexins were also expressed within the glomeruli. These findings indicate that the expression pattern of vascular connexins in the human kidney cortex is very similar to that previously found for mouse and rat kidneys, suggesting that the intrarenal expression pattern of vascular connexins is conserved among the mammalian species. Because of this similarity, and in particular in view of the strong expression of Cx37 and Cx40 in the juxtaglomerular area, we infer that those functions of connexins that have already been demonstrated for rodent kidneys, such as a central role of Cx40 for the development and function of renin-producing cells and for tubuloglomerular signal transmission, might hold for human kidneys as well., (Copyright (c) 2010 S. Karger AG, Basel.)

Background: Mice with deletion of Gsalpha in renin-producing cells (RC/FF mice) have been shown to have greatly reduced renin production and lack of responsiveness of renin secretion to acute stimuli. In addition, young RC/FF mice are hypotensive and have a vasopressin-resistant concentrating defect. In the present study we have determined the long-term effect on renal function, blood pressure, and renal pathology in this low renin and diuretic mouse model., Methods and Results: Urine osmolarity of RC/FF mice was decreased in all age groups. GFR measured at 7, 14 and 20 weeks of age declined progressively. Single nephron GFR similarly declined while fractional proximal fluid absorption was maintained. Expression levels of extracellular matrix proteins (collagen I, IV and fibronectin) and alpha-smooth muscle actin were increased in kidneys of RC/FF mice at 20 weeks, and this was accompanied by focal segmental glomerulosclerosis and periglomerular interstitial fibrosis. RC/FF mice showed a progressive reduction of body weight, an increase in urine albumin excretion, and an increase of blood pressure with aging., Conclusion: A chronic reduction of renin production in mice may be a risk factor in its own right, and does not protect renal function against the profibrotic influence of a chronically elevated urine flow., (Copyright 2010 S. Karger AG, Basel.)

The present study was performed to obtain information about a possible correlation between the activity of the renin-angiotensin system and the stereological features of the macula densa (MD). In normal kidneys, the numbers of angiotensin II AT1 receptors were estimated in MD cells and in the neighboring tubular cells. The total volumes of MD, MD cells, neighboring tubular cells, and the total number of MD cells, were measured in normal and candesartan-treated rats (15 mg/kg/day over 21 days). In the normal kidneys, the relative number of AT1 receptors in MD cells [mean = 0.17 (CV = 0.23)] was significantly (p = 0.03) lower than that in normal tubular cells [0.25 (0.21)]. A significant difference (p < 0.01) was observed in the total volume between MD cells [515 microm(3) (0.14)] and normal tubular cells [984 microm(3) (0.19)]. Candesartan treatment significantly elevated (p < 0.01) the total volume of the MD, whereas the total number of MD cells was increased [from 14.2 (0.11) to 19.5 (0.11)]. The results demonstrated that the transdifferentiation from normal tubular cells to MD cells can be controlled by pharmacological means. The structural features of MD controlled by the renin-angiotensin system may be one of the important factors governing the sensitivity of tubuloglomerular feedback.

Transforming growth factors beta (TGF-betas) are peptides involved in autocrine and paracrine control of cell growth and differentiation. In the kidneys, TGF-beta(2) has been shown to localize specifically in renin-producing cells in various conditions stimulating the renin response. To test in vivo the functional role of TGF-beta(2), the renin response was investigated in mice heterozygous for a null mutation of the TGF-beta(2) gene, which had a twofold reduction in the amount of TGF-beta(2) mRNA. Although the increase in plasma renin concentration triggered by dehydration was not different from wild-type mice, renal renin mRNA and protein levels were higher in mutant mice under hydrated or dehydrated conditions. These data suggest that TGF-beta(2) exerts an inhibitory effect on renin synthesis and release from the juxtaglomerular apparatuses., (Copyright 2002 S. Karger AG, Basel)

Cathepsin B (cathB) is a lysosome cysteine proteinase. It has been suggested to process prorenin to renin in the renin producing juxtaglomerular (JG) cells of the afferent arterioles (AA) of the kidney. Whether cathB expression is regulated similarly to prorenin production is yet unknown. We have measured prorenin and cathB mRNA levels as well as cathB protein levels in renal AA of Sprague-Dawley rats subjected to low (0.02% w/w) salt diet and ramipril treatment (10 mg/kg/day), or to normal (0.6%) or high (4%) salt diet. Prorenin and cathB expression were also analyzed in the JG cell line As4.1. Prorenin mRNA levels in animals on normal (plus ramipril), low or high salt diet correlated as 1:10:0.5, respectively, while cathB mRNA levels correlated as 1:1:0.6, respectively. Treatment of the As4.1 cells with 100 nM phorbol-12-myristate-13-acetate (PMA) for 16 h inhibited prorenin mRNA expression 3-fold relative to the control conditions. CathB mRNA abundance was not different between the PMA treated and the control As4.1 cells. Western analysis of the cathB protein abundance has shown no difference between the rats on normal and low salt diet, and decrease by 50% in the rats on high salt diet. The results of this study suggest that prorenin and cathB gene expression in renal JG cells are differentially regulated.

We have examined the ultrastructural localization of immunoreactive platelet-derived growth factor (PDGF) in Wistar rats injected with cyclosporin A (CyA, 12.5 mg/kg/day) for 4 weeks. CyA injections resulted in a significant increase in serum creatinine (47 +/- 3 vs. 35 +/- 2 mumol/l, p < 0.05) and a reduction in creatinine clearance (0.29 +/- 0.07 vs. 0.53 +/- 0.04 ml/min/100 g b.w., p < 0.01). CyA-treated rats displayed marked hypertrophy and hypergranularity of the juxtaglomerular cells. Morphometric studies showed a significant increase in the number (2.8 +/- 0.3 vs. 1.8 +/- 0.3, p < 0.05) and a 60% increase in the volume of secretion granules within these cells. PDGF was detected exclusively within the secretion granules of the juxtaglomerular cells of the afferent arterioles of CyA-treated animals. We conclude that CyA therapy or its induced haemodynamic alterations result in increased accumulation of PDGF-BB within the secretion granules of the juxtaglomerular cells.

The mesangium is centrally located in the glomerulus and plays an important role in the microcirculation within the glomerulus. In order to reveal the role of the mesangial matrix in the microcirculation, the movement of native anionic ferritin into the juxtaglomerular region was tracked following the intravenous injection of ferritin into rats. The three-dimensional ultrastructures of the mesangial matrix and juxtaglomerular apparatus were studied by conventional scanning and high-resolution scanning electron microscopy after removal of the cellular components. Many ferritin particles were observed from the glomerular capillary to the mesangial matrix, in the mesangial matrix of the juxtaglomerular apparatus and in the tubular lumen of the macula densa after the injection of ferritin. Secretion of macromolecules from the distal tubules seems to be one of the exits from the juxtaglomerular zone. The mesangial matrix was continuous from the vascular pole to the periphery like a branching tree. The intraglomerular mesangial matrix was continuous to the extraglomerular mesangial matrix in the juxtaglomerular region. The mesangial matrix appeared to consist of a polygonal meshwork structure of thin fibrils and pores with high-resolution scanning electron microscopy. The thinnest fiber was approximately 6-nm wide, and the pore size was averaged 20 nm in diameter. We were able to demonstrate the meshwork structure of the mesangial matrix, thus giving the morphological basis of the mesangial matrix to serve as mesangial pathway from the intraglomerular to the extraglomerular mesangial matrix.

Changes in juxtaglomerular (JG; renin-containing) cells in experimental hydronephrosis 1 month after ureteral ligation were investigated with immunoelectron-microscopical techniques. Two types of granules, electron dense (D) and lucent (L), were observed. D type granules were labeled more intensely with gold particles than those of L type. Granules intermediate between D and L types and exocytosis of D types were observed. In the cells containing D types exclusively, gold particles were restricted to the granules, whereas in the cells containing both D and L type granules, the particles were scattered throughout the cytoplasmic cytosol. The authors discuss the mechanisms of renin release in JG cells.

The anticancer drug adriamycin (ADR) is selectively toxic to glomerular cells when administered intravenously (5 mg/kg b.w.) to female MWF/Ztm rats. Recent data have shown that the proteinuria associated with the lesion does not occur in cortical glomeruli, suggesting the selective injury of juxtamedullary glomeruli. In the present study, the effect of ADR on glomerular metabolism was studied with special reference to possible differences between cortical and juxtamedullary glomeruli. On day 7 after ADR treatment, cortical and juxtamedullary glomeruli were separately isolated by the sieving method and 14C glucose oxidation to 14CO2 and the incorporation of 3H proline into macromolecules were measured in vitro and used to study target selective injury in ADR-treated rats compared to control rats. The investigations revealed differences in the response of cortical and juxtamedullary glomeruli to ADR. ADR treatment increased proline incorporation over a 4-hour incubation period in both glomerular populations compared to controls, but the effect was significantly (p less than 0.05) more pronounced in juxtamedullary glomeruli (juxtamedullary: 187 +/- 8% of control; cortical: 167 +/- 4% of control). Glucose oxidation was enhanced after 4 h only in juxtamedullary glomeruli (juxtamedullary: 132 +/- 3% of control; cortical: 82 +/- 10% of control). These data show that glomerular damage caused by ADR is associated with a stimulating effect on glomerular metabolism which is more marked in juxtamedullary than in cortical glomeruli, thus indicating a heterogenous response of different glomerular populations and supporting the concept that the selective damage of juxtamedullary glomeruli accounts for the proteinuria.

Epidermal growth factor (EGF) has previously been found in cells of the thick ascending limb of Henle's loop (TALH) and the first part of the distal convoluted tubule (DCT) of mouse kidney. To define the cellular localization of the mRNA that encodes the protein precursor of EGF, we used high-resolution in situ hybridization. EGF precursor cDNA was hybridized to both paraffin-embedded and frozen sections of mouse kidney. EGF precursor mRNA was detected in cells comprising the TALH and the first part of the DCT. In contrast, tubular cells in the macula densa did not express this specific mRNA. The results indicate that expression of the EGF precursor gene is restricted to specific types of cells in the distal nephron.

An association between the activity of the renin-angiotensin system and the development of spontaneous focal glomerular sclerosis (FGS) in rats has been observed: the onset is preceded by a decrease in plasma renin activity (PRA). This observation was facilitated by the use of Fawn-hooded rats, which develop spontaneous FGS at an early age. Male Fawn-hooded rats develop severe FGS as early as 3 months of age. Male Wistar rats do not develop similar lesions until after 1 year of age. Correspondingly the PRA drops much sooner in Fawn-hooded than in Wistar rats. The low PRA appears to be due to low plasma renin rather than a limitation of the renin substrate, angiotensinogen, which appears to be present in the Fawn-hooded plasma in nonlimiting quantities. In the FH male rats renin content of the kidney drops only after severe glomerular pathology is evident, implying that the low PRA may be due to a decrease in renin secretion by the chromaffin cells of the juxtaglomerular apparatus.

An electron microscopic study of the renal polkissen cells revealed evidence of their participation in the renin angiotensin system. An unusual feature of the cell is the presence of polar nuclear bags (vacuolization) with attached ribosomes. Significantly, a good correlation was observed between vacuolization and plasma renin activity. The latter was created by differing experimental settings, namely restricted sodium intake, hemorrhage, or reduced renal perfusion pressure. These data, plus the finding of secretory granules in these cells, are interpreted as evidence that the polkissen cells are in some way concerned with the regulation of secretion of renin.

The ultrastructure of human renin granules has been studied from a case of Bartter's syndrome. Renin bodies present roundish (R), lobulated (L) or sharply angulated (SA) shapes. The latter are indicative of the highest rates of renin synthesis and thereby of the greatest concentrations of the pressor enzyme. Their singular shape is consistent with the form monoclinic crystals assume when they grow in an isotrophic medium. R granules form owing to filling of Golgian vesicles by renin. R bodies may then coalesce for giving rise to transient L forms. Renin is released through leak from the containing granules into the intracellular space.

A unique case of renovascular hypertension in an asymptomatic, microhematuric 61/2-year-old girl is presented. Abdominal ultrasonographic (UT) and computed tomographic (CT) studies, splenic and renal radionuclide evaluations revealed that a 'boomerang'-shaped spleen, anterior and medial to the left kidney, compressed and flattened its upper pole. Arteriography excluded stenosis of the renal arterial vessels. Renal vein renin ratio of 1.78 and contralateral/caval ratio of 1.13 eventually demonstrated that hypertension was caused by a lateralized renin hypersecretion from the compressed upper pole through left superior and central renal veins. Overactivity of the renin/angiotensin system was presumably due to ischemia of the renal parenchyma extrinsically compressed by the spleen.

A 23-year-old white male was referred for hypertension resistant to triple antihypertensive treatment, with hypokalemia, hyperaldosteronism and elevated levels of circulating plasma renin activity (PRA). Renal angiography and echoscans put in evidence an avascular solid mass at the midlower level of the right kidney. Renal vein catheterization with sampling of blood from the lower branches of the right renal vein showed lateralization of renin secretion from that side. After surgical exeresis, the mass (1.0 cm) was diagnosed as a renal hemangiopericytoma on the basis of light and electron microscopy. Tumor exeresis was followed by a prompt normalization of blood pressure and plasma potassium, with a decrease in PRA and aldosterone. Two months after surgery the patient was still normotensive. Circulating levels of inactive (trypsin-activable) renin were around 60% of the total pool of plasma renin, i.e. much lower than those reported in other cases of renin-secreting tumors. After surgery, inactive and active renin fell in parallel, implying that both were secreted by the tumor. Tumoral PRA responded to postural stimulation, but was unresponsive to acute converting enzyme inhibition, suggesting that sympathetic stimuli were still operative, but the negative feedback inhibition by angiotensin II on renin secretion was lost. Acute converting enzyme inhibition by captopril dropped blood pressure; however, during long-term treatment, the drug (3 X 50 mg/day) was ineffective in terms of either blood pressure normalization or relief of secondary hyperaldosteronism. Acute calcium entry blockade by nifedipine (10 mg p.o.) caused an evident blood pressure drop.

To investigate the relation between renin content in each juxtaglomerular apparatus and reduction of plasma renin activity (PRA) with aging, the PRA and microdissected superficial or juxtamedullary single nephron renin content (SNRC) were determined in 5 young (3-6 months) and 5 aged (13-18 months) rats fed on a normal salt diet. The mean value of the PRA in the aged group was significantly lower than that of the young group. A highly significant correlation was found between the RPA and mean values of the superficial SNRC. The mean values of both the superficial and deep SNRC in the aged rats were significantly lower than those of the corresponding zones in the young rats. It is suggested that decreased synthesis of renin in each juxtaglomerular apparatus is an important factor in the decreased PRA observed with aging.