Renin Overproduction Research Articles

PS-BPB06-2: PIEZO2 EXPRESSION AND ITS ALTERATION BY MECHANICAL FORCES IN MOUSE MESANGIAL CELLS AND RENIN PRODUCING CELLS

The kidney plays a central role in body fluid homeostasis. Cells in the glomeruli and juxtaglomerular apparatus sense mechanical forces and modulate glomerular filtration and renin release. However, details of mechanosensory systems in these cells are unclear. Piezo2 is a recently identified mechanically activated ion channel found in various tissues, especially sensory neurons. Herein, we examined Piezo2 expression and regulation in mouse kidneys. RNAscope in situ hybridization revealed that Piezo2 expression was highly localized in mesangial cells and juxtaglomerular renin producing cells. Immunofluorescence assays detected GFP signals in mesangial cells and juxtaglomerular renin producing cells of Piezo2GFP reporter mice. Piezo2 transcripts were observed in the Foxd1 positive stromal progenitor cells of the metanephric mesenchyme in the developing mouse kidney, which are precursors of mesangial cells and renin producing cells. In a mouse model of dehydration, Piezo2 expression was downregulated in mesangial cells and upregulated in juxtaglomerular renin producing cells, along with the overproduction of renin and enlargement of the area of renin producing cells. Furthermore, the expression of the renin coding gene Ren1 was reduced by Piezo2 knockdown in cultured juxtaglomerular As4.1 cells under static and stretched conditions. These data suggest pivotal roles for Piezo2 in the regulation of glomerular filtration and body fluid balance.

Piezo2 expression and its alteration by mechanical forces in mouse mesangial cells and renin-producing cells

The kidney plays a central role in body fluid homeostasis. Cells in the glomeruli and juxtaglomerular apparatus sense mechanical forces and modulate glomerular filtration and renin release. However, details of mechanosensory systems in these cells are unclear. Piezo2 is a recently identified mechanically activated ion channel found in various tissues, especially sensory neurons. Herein, we examined Piezo2 expression and regulation in mouse kidneys. RNAscope in situ hybridization revealed that Piezo2 expression was highly localized in mesangial cells and juxtaglomerular renin-producing cells. Immunofluorescence assays detected GFP signals in mesangial cells and juxtaglomerular renin-producing cells of Piezo2GFP reporter mice. Piezo2 transcripts were observed in the Foxd1-positive stromal progenitor cells of the metanephric mesenchyme in the developing mouse kidney, which are precursors of mesangial cells and renin-producing cells. In a mouse model of dehydration, Piezo2 expression was downregulated in mesangial cells and upregulated in juxtaglomerular renin-producing cells, along with the overproduction of renin and enlargement of the area of renin-producing cells. Furthermore, the expression of the renin coding gene Ren1 was reduced by Piezo2 knockdown in cultured juxtaglomerular As4.1 cells under static and stretched conditions. These data suggest pivotal roles for Piezo2 in the regulation of glomerular filtration and body fluid balance.

Blockade of myeloid differentiation 2 attenuates diabetic nephropathy by reducing activation of the renin-angiotensin system in mouse kidneys.

Both innate immunity and the renin-angiotensin system (RAS) play important roles in the pathogenesis of diabetic nephropathy (DN). Myeloid differentiation factor 2 (MD2) is a co-receptor of toll-like receptor 4 (TLR4) in innate immunity. While TLR4 is involved in the development of DN, the role of MD2 in DN has not been characterized. It also remains unclear whether the MD2/TLR4 signalling pathway is associated with RAS activation in diabetes. MD2 was blocked using siRNA or the low MW inhibitor, L6H9, in renal proximal tubular cells (NRK-52E cells) exposed to high concentrations of glucose (HG). In vivo, C57BL/6 and MD2-/- mice were injected with streptozotocin to induce Type 1 diabetes and nephropathy. Inhibition of MD2 by genetic knockdown or the inhibitor L6H9 suppressed HG-induced expression of ACE and angiotensin receptors and production of angiotensin II in NRK-52E cells, along with decreased fibrosis markers (TGF-β and collagen IV). Inhibition of the MD2/TLR4-MAPKs pathway did not affect HG-induced renin overproduction. In vivo, using the streptozotocin-induced diabetic mice, MD2 was overexpressed in diabetic kidney. MD2 gene knockout or L6H9 attenuated renal fibrosis and dysfunction by suppressing local RAS activation and inflammation. Hyperglycaemia activated the MD2/TLR4-MAPKs signalling cascade to induce renal RAS activation, leading to renal fibrosis and dysfunction. Pharmacological inhibition of MD2 may be considered as a therapeutic approach to mitigate DN and the low MW inhibitor L6H9 could be a candidate for such therapy.

Cure With Cryoablation of Arterial Hypertension Due to a Renin-Producing Tumor

We herein report on a 20 years old woman with stage I hypertension, who was found to carry a renin-producing tumor (RPT). Due to her young age, the patient underwent screening measurement of plasma renin and aldosterone, abdominal computed tomography (CT) angiography, and selective renal vein renin assessment to identify secondary hypertension. The patient was screened for secondary causes of hypertension and was diagnosed with secondary aldosteronism. Therefore, she underwent an abdominal computed tomography (CT) angiography that was reported as unremarkable. Selective renal vein renin studies showed overproduction of renin in the right kidney and a re-evaluation of her CT allowed detection of an 8-mm mass in her right kidney, suggesting the presence of a RPT. Considering the technical difficulty of renal sparing surgery a CT-guided cryoablation was undertaken, which provided long-term cure of arterial hypertension and normalization of plasma active renin concentration. RPTs usually present with a clinical phenotype featuring stage III and/or malignant hypertension and are held to be exceptionally rare. This case is unique in that it presented with stage I hypertension and a mild clinical phenotype. Moreover, to our knowledge this is the first case of RPTs shown to be safely treated with CT-guided cryoablation and found to be cured at long-term.

Direct Renin Inhibitor is Better than Angiotensin II Receptor Blocker for Intrarenal Arterioles

Background/Aims: We have reported that the long-term administration of angiotensin II receptor blockers (ARBs) induced unusual proliferative changes of renal afferent arteriolar smooth muscle cells (SMCs) in rats, associated with the overproduction of renin. In this study, we examined that a direct renin inhibitor (DRI: Aliskilen; Novartis Pharma Co, USA) might induce different changes on afferent arteriolar walls compared to ARBs. Method: Twenty one 6-weeks-old male spontaneous hypertensive rats (SHRs) were divided into the following three groups: high-dose DRI group (n=7), low-dose DRI group (n=5) and control group (n=9). The rats were fed a standard diet (0.4%NaCl) containing high-dose (150mg/kg/day), low-dose (30mg/kg/day) DRI and without DRI for 12 weeks. The kidneys were examined by histological and immunohistochemical studies. Systolic blood pressure, 24-h urine samples and blood samples were also examined. Results: The afferent arteriolar SMC walls in the two DRI groups showed no proliferative changes. The positive renin expression area was the largest in the high-dose DRI group among the three groups (14.3±4.0µm², 6.7±2.0µm², 2.6±0.9µm²/glomerlus, p=0.020, p=0.008, p=0.017, respectively). Conclusion: The long-term DRI administration increases tissue and circulatory renin; however, afferent arteriolar proliferative changes as shown in ARBs were not induced.

Regulators of angiogenesis in renal ischemia/reperfusion injury in normotensive and hypertensive rats: Effect of tacrolimus

The aim of this study was to evaluate the role of proangiogenic growth factors in an experimental model of ischemia/reperfusion injury (I/R) in both normotensive and hypertensive rats. Renal ischemic injury was induced in transgenic rats rendered hypertensive due to renin overproduction [TGR (mREN-2)-27] and in normotensive Hannover Sprague-Dawley rats (HanSD). Animals were treated for 12 weeks with either tacrolimus (TAC, 0.1 mg/kg per day, intramuscularly [IM]) or placebo. After 12 weeks, kidneys were harvested for morphologic, immunohistochemical, and RT-PCR analysis. Both normotensive and hypertensive untreated rats developed significantly greater proteinuria and glomerulosclerosis compared with TAC-treated rats. Immunohistologically, TGR showed higher basic fibroblast growth factor (bFGF) protein expression compared with normotensive HanSD. TAC-treated rats had higher bFGF protein expression than untreated rats. Vascular endothelial growth factor (VEGF) protein expression in glomeruli was more increased in TGR after I/R than in sham-operated animals. TAC-treated TGR hosts developed higher VEGF mRNA expression compared with both untreated and sham groups; however, there were no differences between treated and untreated normotensive HanSD animals. bFGF is involved in the fibrogenesis induced by hypertension and I/R injury. The nature of the increase in proangiogeneic growth factor expression among tacrolimus-treated animals remains to be elucidated.

Effect of sirolimus on renal ischaemia/ reperfusion injury in normotensive and hypertensive rats

Abstract Background. Renal ischaemia/reperfusion (I/R) injury and hypertension represent major alloantigen-independent factors contributing to the development of chronic allograft nephropathy of renal allografts. In the present study, we investigated the effect of the antiproliferative immunosuppressant, sirolimus (SIR), in a model of accelerated renal injury in hypertensive transgenic rats (TGRs). Twenty anaesthetized uninephrectomized TGRs with renin overproduction [TGR(mREN2)27] and 20 normotensive Han SD (SD) rats as genetic controls had their renal pedicles clipped for 45 min and were subsequently treated with either SIR (0.5 mg/kg per day, orally) or placebo (n= 10 in each group) for 16 weeks, after which time the kidneys were harvested for morphological and immunohistochemical analysis. High-renin hypertension aggravated the functional and structural changes induced by I/R in SD animals: both SIR-treated and untreated TGRs exhibited significantly greater proteinuria and suffered from more severe glomerulosclerosis (P < 0.01) and vasculopathy (P < 0.01), as well as compensatory renal hypertrophy (P < 0.01) and tissue TGF-β1 expression, than both normotensive SD groups (P < 0.01). SIR-treated SD rats showed reduced proteinuria (P < 0.01), glomerulosclerosis (P < 0.01), and TGF-β1 expression in the glomerular epithelium and proximal tubuli (P < 0.05) compared with placebo-treated SD rats. SIR-treated TGRs had significantly lower proteinuria at week 4 after I/R (P < 0.01) than placebo-treated TGRs, but there were no significant differences thereafter. Morphological patterns were similar in treated and untreated TGRs at week 16. High-renin-induced hypertension aggravated the renal injury induced by I/R. Sirolimus treatment ameliorated some late functional and morphological changes induced by I/R injury in hypertensive TGRs but, particularly, in normotensive SD rats.

Effect of sirolimus on renal ischaemia/reperfusion injury in normotensive and hypertensive rats.

Renal ischaemia/reperfusion (I/R) injury and hypertension represent major alloantigen-independent factors contributing to the development of chronic allograft nephropathy of renal allografts. In the present study, we investigated the effect of the anti-proliferative immunosuppressant, sirolimus (SIR), in a model of accelerated renal injury in hypertensive transgenic rats (TGRs). Twenty anaesthetized uninephrectomized TGRs with renin overproduction [TGR(mREN2)27] and 20 normotensive Han SD (SD) rats as genetic controls had their renal pedicles clipped for 45 min and were subsequently treated with either SIR (0.5 mg/kg per day, orally) or placebo ( n=10 in each group) for 16 weeks, after which time the kidneys were harvested for morphological and immunohistochemical analysis. High-renin hypertension aggravated the functional and structural changes induced by I/R in SD animals: both SIR-treated and untreated TGRs exhibited significantly greater proteinuria and suffered from more severe glomerulosclerosis ( P<0.01) and vasculopathy ( P<0.01), as well as compensatory renal hypertrophy ( P<0.01) and tissue TGF-beta1 expression, than both normotensive SD groups ( P<0.01). SIR-treated SD rats showed reduced proteinuria ( P<0.01), glomerulosclerosis ( P<0.01), and TGF-beta1 expression in the glomerular epithelium and proximal tubuli ( P<0.05) compared with placebo-treated SD rats. SIR-treated TGRs had significantly lower proteinuria at week 4 after I/R ( P<0.01) than placebo-treated TGRs, but there were no significant differences thereafter. Morphological patterns were similar in treated and untreated TGRs at week 16. High-renin-induced hypertension aggravated the renal injury induced by I/R. Sirolimus treatment ameliorated some late functional and morphological changes induced by I/R injury in hypertensive TGRs but, particularly, in normotensive SD rats.

The genetics of pre-eclampsia: a feto-placental or maternal problem?

Pre-eclampsia is a potentially life-threatening disease of women during pregnancy leading to hypertension and proteinuria. It affects 1 in 15 pregnancies but, despite intense research efforts, the cause of the disease remains mysterious. Because pre-eclampsia only occurs during pregnancy and its symptoms resolve after delivery, factors from the placenta are thought to be involved. The role of the placenta could be production of 'abnormal' factors that initiate widespread inflammation and vaso-constriction. Alternatively, because the placenta normally contributes to maternal cardiovascular adaptations of pregnancy, it may be that normal placental functions fail in pre-eclampsia or that susceptibilities in the mother to hypertensive, vascular and/or renal disease prevent the appropriate normal responses to them. The potential contributions of both maternal and fetal genes to the onset of the disease have complicated the genetic analysis of the disease in humans. Recent studies have identified strains of transgenic and mutant mice that develop the hallmark features of pre-eclampsia-like disease - gestational hypertension, proteinuria and kidney lesions (glomerulosclerosis). Comparison of three different mouse models suggests that pre-eclampsia can be initiated by at least three independent mechanisms: pre-existing borderline maternal hypertension that is exacerbated by pregnancy (BPH/5 strain of mice), elevated levels of the vasoconstrictor angiotensin II in the maternal circulation by placental over-production of renin (renin/angiotensinogen transgenic mice), and placental pathology (p57Kip2 mutant mice). These findings imply that the pathogenesis of pre-eclampsia cannot be explained by a single mechanism. Therefore, segregation of the human disease into different subtypes may be a key first step in identifying genetic risk factors.

Laparoscopic renal cryoablation: impact on renal function and blood pressure

Objectives. To evaluate the renal function and blood pressure outcomes after laparoscopic renal cryotherapy. Laparoscopic renal cryoablation is a developmental minimally invasive modality for the treatment of renal neoplasms. After cryotherapy, a segment of renal parenchyma is rendered ischemic/necrotic and left in situ. It is currently unknown whether this may trigger renin overproduction and thus renin-mediated hypertension. Methods. Data are presented for 22 of 56 treated patients, each of whom completed a minimum follow-up of 6 months. The data were obtained from patient charts, phone interviews, and/or questionnaires. These results were statistically compared over time by paired t tests. Results. The mean follow-up was 20.6 months. No significant differences were found between the preoperative and most recent postoperative serum creatinine (sCr) levels (1.13 and 0.91 mg/dL, respectively), systolic and diastolic blood pressure values (135.6 versus 131.2 mm Hg and 78 versus 72.7 mm Hg, respectively), or in the estimated creatinine clearance ( P <0.05). The number or dose of antihypertensive medications did not change during the follow-up period for any patient. In 3 patients with a solitary kidney, the blood pressure and sCr values remained unchanged (mean preoperative sCr 1.43 mg/dL and mean postoperative sCr after a minimum of 6 months 1.33 mg/dL). Conclusions. Laparoscopic renal cryoablation did not have a deleterious impact on renal function or blood pressure during a mean follow-up of 20.6 months.

First report of active renin in rat amniotic fluid.

1. Epidemiological studies indicate that a reduced birthweight increases the likelihood of human cardiovascular disease later in life. The role of hormonal factors in this finding is not known. Given that angiotensin II is believed to be a fetal regulator of growth, we have examined in the hypertensive Ren-2 transgenic rat whether it has active renin in its amniotic fluid and whether this is associated with fetal underdevelopment. 2. We found that while the Sprague-Dawley rat contained no active renin in its amniotic fluid near term (20 days), Ren-2 amniotic fluid contains high levels of active renin and is associated with a reduced fetal weight. 3. This is the first report of active renin in the rat and allows the possibility that renin overproduction plays a role in reduced fetal growth and the prenatal 'programming' of essential hypertension that has been proposed to occur in humans.

Expression of neuronal type nitric oxide synthase and renin in the juxtaglomerular apparatus of angiotensin type-1a receptor gene-knockout mice

Angiotensin type-1a (AT1a) receptor gene-knockout (AT1a-/-) mice exhibit chronic hypotension and renin overproduction. In the kidneys of AT1a-/- mice, the activity of neuronal type nitric oxide synthase (N-NOS) was histochemically detected by nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase (NADPHd) reaction combined with N-NOS immunohistochemistry. The localization of renin was detected by immunohistochemistry and the results were analyzed morphometrically. The levels of N-NOS and renin mRNA in the renal cortical tissue were determined by reverse transcription-PCR and Northern blot analysis, respectively. In the renal sections from wild-type mice, NADPHd activity and N-NOS immunoreactivity were localized to the discrete region of the macula densa in contact with the parent glomerulus. In contrast, N-NOS-positive macula densa cells were distributed beyond the original location of the macula densa, occasionally extending to the opposite side of the distal tubules. The mean number of N-NOS positive macula densa cells was significantly increased in AT1a-/- mice (186 per 100 glomeruli) compared with wild-type mice (65 per 100 glomeruli). AT1a-/- mice showed 1.4-times higher N-NOS mRNA levels in the renal cortical tissues than wild-type mice. The plasma renin activity was significantly higher in AT1a-/- mice (205.5 +/- 26.1 ng/ml/hr) than in wild-type mice (8.0 +/- 0.2 ng/ml/hr). The renin-positive areas per glomerulus and renal renin gene expression were 12-times and 2.6-times higher in AT1a-/- mice than in wild-type mice, respectively. These abnormalities, however, were less remarkable in AT1a-/- mice compared with angiotensinogen-knockout mice. When AT1a-/- mice were fed a high-salt diet, the signal intensity of the NADPHd reaction and the number of positively-stained macula densa cells were significantly decreased. The levels of renal cortical N-NOS mRNA were also suppressed by the treatment. Dietary salt loading produced a parallel decrease in plasma renin activity, renal renin-immunoreactive areas, and the levels of renin mRNA without affecting systemic blood pressure. These results provide evidence for the possible involvement of N-NOS at the macula densa in the increased renin production in AT1a-/- mice.

Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. 1962.

A new syndrome, characterized by hypertrophy and hyperplasia of the juxtaglomerular apparatus of the kidneys, aldosteronism resulting from adrenal cortical hyperplasia, and persistently normal blood pressure is described in two patients. Overproduction of aldosterone could not be prevented by sodium loading or by administration of albumin intravenously; it was associated with hypokalemic alkalosis and Pitressin-resistant impairment of urinary concentrating ability. In both subjects, increased amounts of circulating angiotensin were demonstrated; infusion of angiotensin II produced rises of blood pressure in both subjects considerably less than the rises induced by comparable doses in normal subjects. The sequence of events, (1) primary resistance to the pressor action of angiotensin, (2) compensatory overproduction of renin and thus of angiotensin, and (3) stimulation of adrenal cortex by angiotensin is consistent with all the information available about the syndrome.

Altered Nuclear Protein Binding to the First Intron of the Renin Gene of the Spontaneously Hypertensive Rat

We and others have reported elevated levels of renin mRNA in extrarenal tissues of the spontaneously hypertensive rat (SHR) of the Okamoto strain. We hypothesise that this is due to mutations we have found in putative, cis-regulatory regions in the first intron of its renin gene. Here we report two G-A mutations at position +502 and +934 of the first intron of the SHR renin gene, when compared to normotensive Wistar Kyoto (WKY) and Sprague Dawley (SD) rats. These mutations fall within consensus sequences for the well described E2A and peroxisome proliferator-activated receptor (PPAR) transcription factors. We used electrophoretic mobility shift assays to determine if these mutations alter the pattern or affinity of nuclear protein binding to oligonucleotides homologous to these regions of the renin gene. Both mutations significantly altered the intensity and pattern of nuclear protein binding to oligonucleotides homologous with the renin gene regions bearing these putative transcription factor binding sites. Thus these mutations have the potential to alter the type and/or affinity of transcriptional factors for the SHR renin gene in vivoand result in renin overproduction at an extra-renal tissue site subserving blood pressure control

Altered age-dependent modulation of tissue renin messenger RNA levels in the spontaneously hypertensive rat.

To evaluate the possible role of tissue renin overproduction in the pathogenesis and time course of hypertension development in the spontaneously hypertensive rat (SHR) of the Okamoto strain by measuring tissue renin gene expression at different stages of hypertension development. Measurements of kidney, adrenal gland and brain stem renin messenger RNA (mRNA) levels were performed in SHR aged 4, 12, 20 and 36 weeks and in age-matched normotensive Wistar-Kyoto (WKY) rats. A fully quantitative, competitive reverse transcriptase polymerase chain reaction method was used to measure tissue renin mRNA levels. Plasma renin concentrations were measured by radioimmunoassay. Compared with age-matched WKY rats, renin mRNA levels in the adrenal gland of SHR were significantly higher at ages 4, 12 and 36 weeks. Brain stem renin mRNA levels were significantly higher in SHR than in WKY rats at ages 4, 12 and 20 weeks. In contrast, renal renin mRNA levels were consistently lower in SHR at all ages, as were plasma renin concentrations. The present study indicates an important role for renin gene expression both in adrenal and in brain stem tissues in the pathogenesis of hypertension in SHR. Adrenal and brain renin-angiotensin systems may interact with each other synergistically in the development and maintenance of hypertension in SHR. Suppressed renal renin gene expression could then be an indirect consequence of the amplified renin-angiotensin system in the adrenal gland and in the brain or a baroreceptor-mediated consequence of its hypertension.

Low-Dose Captopril Scintigraphy in the Evaluation of Renovascular Hypertension

This study compared the results of renal scintigraphy with simultaneous administration of Tc-99m DTPA and I-131 Hippuran (before and after 25 mg of oral captopril) with the results of the renal arteriogram and renal vein renins (before and after the administration of 25 mg of oral captopril) to evaluate the sensitivity and specificity of renal scintigraphy in the diagnosis of renovascular hypertension. The results of 21 consecutive patients suspected of having renovascular hypertension who underwent scintigraphy and renal arteriography were analyzed. Renal scintigraphy postcaptopril detected all the cases of renovascular hypertension (eight patients) plus two additional patients who had significant renovascular stenosis but no renin overproduction. The results indicate that the renal scintigram, before and after the administration of captopril, is an accurate and sensitive test for the detection of renovascular hypertension and should be used as a screening procedure before arteriography is considered.

Renin-Secreting Clear Cell Carcinoma of the Kidney

A young woman with mild to moderate hypertension and normal PRA, serum potassium levels, and urinary aldosterone excretion rate was found to have a renal tumor by selective renal arteriogram. Renal vein renin activity indicated an increased production of renin from the kidney containing the tumor. At surgery, a clear cell carcinoma of the kidney was found that contained renin activity in excess of the surrounding kidney tissue. The renin activity appeared identical to human kidney renin. Previous renin-producing tumors have been associated with severe hypertension, elevated plasma renin activity, hypokalemia, and elevated urinary aldosterone excretion. This case should call attention to the renin-secreting tumor as a cause of even mild hypertension.

The adrenal cortex and the kidney

The adrenal cortex regulates renal function in a number of important ways; indeed, normal renal function cannot be understood without recognition of such regulation. Well-recognized examples of such regulation are the control of body fluid tonicity through regulation of urinary solute concentration-a function controlled by vasopressin, but secondarily and importantly by the adrenal cortex-and control of body sodium-a function controlled primarily by renal tubular sodium reabsorption but regulated by sodium-retaining steroids. The kidney can regulate adrenal function by changing reabsorption of sodium and secretion of potassium, and also by release of renin. The target of such regulation is the secretion of aldosterone, which may be influenced by body fluid volume, potassium ion and angiotensin II. Because of these interrelationships, the pathophysiology of certain disease states may be described as aberrations in feedback loops between adrenal cortex and kidney. In this paper we will consider this system in some detail, and attempt to explain four disorders as examples of errors in control. In the form of primary aldosteronism resulting from hyperplasia of all adrenal cortical tissue, overproduction of aldosterone persists in the absence of all known stimulatory factors. In renovascular hypertension, angiotensin and aldosterone production may persist despite systemic hypertension. In the non-salt-losing form of the adrenogenital syndrome of congenital adrenal hyperplasia without treatment, failure of feedback inhibition by Cortisol may result in overproduction of adrenocorticotropic hormone (ACTH) which, in turn, may lead to overproduction of progesterone. Progesterone may cause sodium loss and overproduction of renin and aldosterone while blocking their effects. In the syndrome of juxtaglomerular hyperplasia with normal blood pressure, overproduction of renin may result from unresponsiveness of blood vessels leading to a lack of feedback inhibition by pressure rise. Under certain circumstances sodium loss can potentiate both the overproduction and the unresponsiveness. Excessive renin leads to aldosteronism and potassium loss.

Juvenile hypertension caused by overproduction of renin within a renal segment

A 6 8/12-year-old boy with severe hypertension was found to have stenosis of a segmental renal artery, which caused overproduction of renin and secondary hyperaldosteronism. Renal vein catheterization failed to demonstrate a significant difference in right and left renal vein renin activities; only at surgery was the diagnosis of segmental overproduction of renin confirmed. Pathologic studies disclosed juxtaglomerular cell hyperplasia limited to the affected segment and provided corroborative evidence of the segmental source of the hyperreninemia.

Bartter's syndrome and erythrocytosis

We describe a patient, known since 1960, with Bartter's syndrome and erythrocytosis. The diagnosis was made on the basis of hypokalemic alkalosis, hyperplasia of the juxtaglomerular apparatus, resistance to the presser effect of angiotensin, extremely high plasma renin activity and normal blood pressure. This patient had a normal pattern of aldosterone excretion and a decreased ability of the kidneys to preserve potassium adequately. The nephropathy was characterized by a normal glomerular filtration rate, an irreversible inability of the kidney to concentrate the urine and a reversible inability of the kidney to excrete an acid load. The kidneys were enlarged; a biopsy specimen revealed hyperplasia of the juxtaglomerular apparatus, hyperplasia of the macula densa and an extensive fibrosis of the medulla. The intracellular red cell sodium level was elevated and the potassium level decreased during potassium depletion; they returned to nearly normal levels after adequate potassium supplementation. As a feature previously unknown in this syndrome the patient had a distinct erythrocytosis. There was an elevated red cell volume and an increase in the reticulocyte count after the oral administration of iron despite a high hemoglobin level. The erythropoietic activity of the serum, measured by bioassay, was increased to 10 times normal. We presume that there is a simultaneous overproduction of renin and erythropoietin in this patient with Bartter's syndrome. The stimulus for this over-production cannot be defined exactly. Our findings support the view that the primary defect in Bartter's syndrome is an impaired reabsorption of sodium in the ascending limb of Henle's loop. The case is further evidence for the juxtaglomerular apparatus being the production site of both renin and erythropoietin.