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Korean Journal of Pediatrics Apr 2019The most common type of refractory hypertension found in children is secondary hypertension, which is a potentially curable disease. Reninoma, a renin-secreting...
The most common type of refractory hypertension found in children is secondary hypertension, which is a potentially curable disease. Reninoma, a renin-secreting juxtaglomerular cell tumor, is a rare cause of severe hypertension that is usually diagnosed in adolescents and young adults. Surgical resection of the tumor completely cures the hypertension of patients with reninoma. The typical clinical presentation of reninoma includes hypokalemia, metabolic alkalosis, and features secondary to the increased activation of the renin-angiotensin system without renal artery stenosis. We report a case of reninoma in a female adolescent with a typical clinical presentation, in which surgical removal of the tumor completely cured hypertension. We discuss here the clinical features, imaging studies, and immunohistochemical examination of the tumor used to establish the diagnosis of reninoma and for the management of the condition.
PubMed: 30376707
DOI: 10.3345/kjp.2018.06926 -
Frontiers in Pharmacology 2019Chronic kidney disease (CKD) is characterized by renal dysfunction, which is a common feature of other major diseases, such as hypertension and diabetes. Unilateral...
Chronic kidney disease (CKD) is characterized by renal dysfunction, which is a common feature of other major diseases, such as hypertension and diabetes. Unilateral ureteral obstruction (UUO) has been used as a model of CKD in experimental animals and consists of total obstruction of one kidney ureter. The UUO decreases renal blood flow, which promotes the synthesis of renin in the juxtaglomerular apparatus, the first step in renin-angiotensin system (RAS) cascade. RAS induces inflammation and remodeling, along with reduced renal function. However, it remains unknown whether intrarenal RAS (iRAS) is activated in early stages of CKD. Our objective was to characterize different iRAS components in the renal cortex and in the medulla in an early phase of UUO. Male C57BL/6 mice (8-12 weeks old) were subjected to UUO in the left kidney, or to sham surgery, and were euthanized after 7 days ( = 5/group). Renal function, renal inflammatory/remodeling processes, and iRAS expression were evaluated. UUO increased plasma creatinine, right renal hypertrophy (9.08 ± 0.31, < 0.05 vs. Sham), and tubular dilatation in the left kidney cortex (42.42 ± 8.19µm, < 0.05 vs. Sham). This correlated with the increased mRNA of IL-1β (1.73 ± 0.14, < 0.01 vs. Sham, a pro-inflammatory cytokine) and TGF-β1 (1.76 ± 0.10, < 0.001 vs. Sham, a pro-fibrotic marker). In the renal cortex of the left kidney, UUO increased the mRNA and protein levels of renin (in 35% and 28%, respectively, P < 0.05 vs. Sham). UUO decreased mRNA and protein levels for the (pro)renin receptor in the renal medulla (0.67 ± 0.036 and 0.88 ± 0.028, respectively, < 0.05 vs. Sham). Our results suggest that modulation of iRAS components depends on renal localization and occurs in parallel with remodeling and pro-inflammatory/pro-fibrotic mechanisms.
PubMed: 31803050
DOI: 10.3389/fphar.2019.01314 -
Environmental Health Perspectives Aug 1984Aminoglycoside-induced proteinuria may result from general renal damage or may reflect alterations in specific steps in the renal handling of proteins. To differentiate... (Review)
Review
Aminoglycoside-induced proteinuria may result from general renal damage or may reflect alterations in specific steps in the renal handling of proteins. To differentiate between the two possibilities, experiments were designed to quantify the effects of nephrotoxic doses of gentamicin, tobramycin and netilmicin in the intact rat, isolated perfused rat kidney (IPK) and kidney slices using the cationic low molecular weight protein lysozyme as a model protein. Each aminoglycoside was administered IP to male Wistar rats (15 or 30 mg/kg/day) for 5 or 7 days. Scanning and transmission electron microscopy indicated that gentamicin and tobramycin induced a decrease in the number and diameter of endothelial fenestrae and degranulation of the myoepithelioid cells of the juxtaglomerular apparatus. Concurrently, gentamicin and tobramycin decrease the glomerular sieving coefficient of lysozyme from 0.8 to 0.6 and 0.5, respectively. Netilmicin did not affect the percentage reabsorption of lysozyme whereas gentamicin and tobramycin induced a 50% decrease in lysozyme reabsorption by the IPK. Gentamicin and tobramycin decreased equally lysozyme degradation by the IPK; this decrease was time- and dose-dependent when evaluated in slices from renal cortex. Perfusion of rat kidneys with gentamicin induced a dose-dependent decrease in reabsorption and catabolism of lysozyme. In conclusion, these studies demonstrate that polycationic aminoglycosides alter ultrastructure and glomerular permeability, tubular reabsorption and intracellular digestion of proteins.
Topics: Absorption; Acetylglucosaminidase; Aminoglycosides; Animals; Anti-Bacterial Agents; Biotransformation; Glomerular Filtration Rate; Kidney; Kidney Tubules; Lysosomes; Male; Muramidase; Proteinuria; Rats
PubMed: 6389114
DOI: 10.1289/ehp.8457293 -
American Journal of Physiology. Renal... Aug 2006ATP release from macula densa (MD) cells into the interstitium of the juxtaglomerular (JG) apparatus (JGA) is an integral component of the tubuloglomerular feedback...
ATP release from macula densa (MD) cells into the interstitium of the juxtaglomerular (JG) apparatus (JGA) is an integral component of the tubuloglomerular feedback (TGF) mechanism that controls the glomerular filtration rate. Because the cells of the JGA express a number of calcium-coupled purinergic receptors, these studies tested the hypothesis that TGF activation triggers a calcium wave that spreads from the MD toward distant cells of the JGA and glomerulus. Ratiometric calcium imaging of in vitro microperfused isolated JGA-glomerulus complex dissected from rabbits was performed with fluo-4/fura red and confocal fluorescence microscopy. Activation of TGF by increasing tubular flow rate at the MD rapidly produced a significant elevation in intracellular Ca(2+) concentration ([Ca(2+)](i)) in extraglomerular mesangial cells (by 187.6 +/- 45.1 nM) and JG renin granular cells (by 281.4 +/- 66.6 nM). Subsequently, cell-to-cell propagation of the calcium signal at a rate of 12.6 +/- 1.1 microm/s was observed upstream toward proximal segments of the afferent arteriole and adjacent glomeruli, as well as toward intraglomerular elements including the most distant podocytes (5.9 +/- 0.4 microm/s). The same calcium wave was observed in nonperfusing glomeruli, causing vasoconstriction and contractions of the glomerular tuft. Gap junction uncoupling, an ATP scavenger enzyme cocktail, and pharmacological inhibition of P(2) purinergic receptors, but not adenosine A(1) receptor blockade, abolished the changes in [Ca(2+)](i) and propagation of the calcium wave. These studies provided evidence that both gap junctional communication and extracellular ATP are integral components of the TGF calcium wave.
Topics: Adenosine Triphosphate; Animals; Arterioles; Calcium; Feedback; Female; Gap Junctions; Juxtaglomerular Apparatus; Kidney Glomerulus; Kidney Tubules; Rabbits; Receptor, Adenosine A1; Receptors, Purinergic P2; Signal Transduction; Time Factors; Vasoconstriction
PubMed: 16495210
DOI: 10.1152/ajprenal.00425.2005 -
Journal of the American Society of... Aug 2016Nitric oxide (NO) is an important negative modulator of tubuloglomerular feedback responsiveness. We recently found that macula densa expresses α-, β-, and γ-splice...
Nitric oxide (NO) is an important negative modulator of tubuloglomerular feedback responsiveness. We recently found that macula densa expresses α-, β-, and γ-splice variants of neuronal nitric oxide synthase 1 (NOS1), and NOS1β expression in the macula densa increases on a high-salt diet. This study tested whether upregulation of NOS1β expression in the macula densa affects sodium excretion and salt-sensitive hypertension by decreasing tubuloglomerular feedback responsiveness. Expression levels of NOS1β mRNA and protein were 30- and five-fold higher, respectively, than those of NOS1α in the renal cortex of C57BL/6 mice. Furthermore, macula densa NO production was similar in the isolated perfused juxtaglomerular apparatus of wild-type (WT) and nitric oxide synthase 1α-knockout (NOS1αKO) mice. Compared with control mice, mice with macula densa-specific knockout of all nitric oxide synthase 1 isoforms (MD-NOS1KO) had a significantly enhanced tubuloglomerular feedback response and after acute volume expansion, significantly reduced GFR, urine flow, and sodium excretion. Mean arterial pressure increased significantly in MD-NOS1KO mice (P<0.01) but not NOS1flox/flox mice fed a high-salt diet. After infusion of angiotensin II, mean arterial pressure increased by 61.6 mmHg in MD-NOS1KO mice versus 32.0 mmHg in WT mice (P<0.01) fed a high-salt diet. These results indicate that NOS1β is a primary NOS1 isoform expressed in the macula densa and regulates the tubuloglomerular feedback response, the natriuretic response to acute volume expansion, and the development of salt-sensitive hypertension. These findings show a novel mechanism for salt sensitivity of BP and the significance of tubuloglomerular feedback response in long-term control of sodium excretion and BP.
Topics: Animals; Hypertension; Juxtaglomerular Apparatus; Male; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type I; Sodium Chloride, Dietary
PubMed: 26647426
DOI: 10.1681/ASN.2015050515 -
Hypertension (Dallas, Tex. : 1979) Feb 2013Chronic challenge of renin-angiotensin causes recruitment of renin-producing cells in the kidney along the media layer of afferent arterioles and hypertrophy of cells in...
Chronic challenge of renin-angiotensin causes recruitment of renin-producing cells in the kidney along the media layer of afferent arterioles and hypertrophy of cells in the juxtaglomerular apparatus. This study aimed to define the role of nitric oxide (NO) with regard to the recruitment pattern of renin-producing cells and to the possible pathways along which NO could act. We considered the hypothesis that endothelium-derived NO acts via NO-sensitive guanylate cyclase. Mice were treated with low-salt diet in combination with the angiotensin I-converting enzyme inhibitor enalapril for 3 weeks, which led to a 13-fold increase in renin expression associated with marked recruitment of renin cells in afferent arterioles and hypertrophy of the juxtaglomerular apparatus in wild-type mice. In wild-type mice additionally treated with the nonselective NO synthase inhibitor L-NAME, the recruitment of renin-expressing cells along the afferent arterioles was absent and juxtaglomerular hypertrophy was diminished. An almost identical attenuation of renin cell recruitment as with L-NAME treatment in wild-type mice was found in mice lacking the endothelial isoform of NO synthase. Treatment of mice lacking NO-sensitive guanylate cyclase in renin-expressing cells and preglomerular smooth muscle cells with low-salt diet in combination with the angiotensin I-converting enzyme inhibitor enalapril for 3 weeks produced juxtaglomerular hypertrophy like in wild-type mice, but no recruitment in afferent arterioles. These findings suggest that endothelium-derived NO and concomitant formation of cGMP in preglomerular renin cell precursors supports recruitment of renin-expressing cells along preglomerular vessels, but not in the juxtaglomerular apparatus.
Topics: Animals; Blood Pressure; Endothelium, Vascular; Enzyme Inhibitors; Guanylate Cyclase; Juxtaglomerular Apparatus; Kidney; Mice; Mice, Knockout; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type III; Renin; Signal Transduction
PubMed: 23297374
DOI: 10.1161/HYPERTENSIONAHA.111.00221 -
American Journal of Physiology. Renal... Apr 2009Tubuloglomerular feedback (TGF) and the myogenic mechanism control afferent arteriolar diameter in each nephron and regulate blood flow. Both mechanisms generate...
Tubuloglomerular feedback (TGF) and the myogenic mechanism control afferent arteriolar diameter in each nephron and regulate blood flow. Both mechanisms generate self-sustained oscillations, the oscillations interact, TGF modulates the frequency and amplitude of the myogenic oscillation, and the oscillations synchronize; a 5:1 frequency ratio is the most frequent. TGF oscillations synchronize in nephron pairs supplied from a common cortical radial artery, as do myogenic oscillations. We propose that electrotonic vascular signal propagation from one juxtaglomerular apparatus interacts with similar signals from other nephrons to produce synchronization. We tested this idea in tubular-vascular preparations from mice. Vascular smooth muscle cells were loaded with a fluorescent voltage-sensitive dye; fluorescence intensity was measured with confocal microscopy. Perfusion of the thick ascending limb activated TGF and depolarized afferent arteriolar smooth muscle cells. The depolarization spread to the cortical radial artery and other afferent arterioles and declined with distance from the perfused juxtaglomerular apparatus, consistent with electrotonic vascular signal propagation. With a mathematical model of two coupled nephrons, we estimated the conductance of nephron coupling by fitting simulated vessel diameters to experimental data. With this value, we simulated nephron pairs to test for synchronization. In single-nephron simulations, the frequency of the TGF oscillation varied with nephron length. Coupling nephrons of different lengths forced TGF frequencies of both pair members to converge to a common value. The myogenic oscillations also synchronized, and the synchronization between the TGF and the myogenic oscillations showed an increased stability against parameter perturbations. Electronic vascular signal propagation is a plausible mechanism for nephron synchronization. Coupling increased the stability of the various oscillations.
Topics: Animals; Arterioles; Computer Simulation; Glomerular Filtration Rate; Homeostasis; In Vitro Techniques; Juxtaglomerular Apparatus; Membrane Potentials; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence, Multiphoton; Models, Biological; Muscle, Smooth, Vascular; Oscillometry; Perfusion; Renal Circulation; Signal Transduction; Time Factors
PubMed: 19116241
DOI: 10.1152/ajprenal.90669.2008 -
Nefrologia : Publicacion Oficial de La... 2015Arterial hypertension is a highly prevalent disease and its secondary causes must always be kept in mind because the treatment and prognosis differ between these and... (Review)
Review
Arterial hypertension is a highly prevalent disease and its secondary causes must always be kept in mind because the treatment and prognosis differ between these and essential hypertension. Here we present the first reported case in Argentina of a 21-year-old patient with arterial hypertension and hypokalaemia due to a renin-secreting juxtaglomerular cell tumour, which was diagnosed after seven years of development.
Topics: Female; Humans; Hyperaldosteronism; Hypertension, Renal; Hypokalemia; Juxtaglomerular Apparatus; Kidney Neoplasms; Myoepithelioma; Nephrectomy; Pregnancy; Pregnancy Complications, Neoplastic; Renin; Young Adult
PubMed: 25611839
DOI: 10.3265/Nefrologia.pre2014.Sep.12623 -
American Journal of Physiology. Renal... Nov 2005PGE(2) and PGI(2) stimulate renin secretion and cAMP accumulation in juxtaglomerular granular (JG) cells. We addressed, at the single-cell level, the receptor subtypes...
PGE(2) and PGI(2) stimulate renin secretion and cAMP accumulation in juxtaglomerular granular (JG) cells. We addressed, at the single-cell level, the receptor subtypes and intracellular transduction mechanisms involved. Patch clamp was used to determine cell capacitance (C(m)), current, and membrane voltage in response to PGE(2), EP2 and EP4 receptor agonists, and an IP receptor agonist. PGE(2) (0.1 micromol/l) increased C(m) significantly, and the increase was abolished by intracellular application of the protein kinase A antagonist Rp-8-CPT-cAMPS. EP2-selective ligands butaprost (1 micromol/l), AE1-259-01 (1 nmol/l), EP4-selective agonist AE1-329 (1 nmol/l), and IP agonist iloprost (1 micromol/l) significantly increased C(m) mediated by PKA. The EP4 antagonist AE3-208 (10 nmol/l) blocked the effect of EP4 agonist but did not alter the response to PGE(2). Application of both EP4 antagonist and EP2-antagonist AH-6809 abolished the effects of PGE(2) on C(m) and current. EP2 and EP4 ligands stimulated cAMP formation in JG cells. PGE(2) rapidly stimulated renin secretion from superfused JG cells and diminished the membrane-adjacent granule pool as determined by confocal microscopy. The membrane potential hyperpolarized significantly after PGE(2), butaprost, AE1-329 and AE1-259 and outward current was augmented in a PKA-dependent fashion. PGE(2)-stimulated outward current, but not C(m) change, was abolished by the BK(Ca) channel inhibitor iberiotoxin (300 nmol/l). EP2 and EP4 mRNA was detected in sampled JG cells, and the preglomerular and glomerular vasculature was immunopositive for EP4. Thus IP, EP2, and EP4 receptors are associated with JG cells, and their activation leads to rapid PKA-mediated exocytotic fusion and release of renin granules.
Topics: Animals; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Exocytosis; Juxtaglomerular Apparatus; Male; Membrane Potentials; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Renin
PubMed: 15985651
DOI: 10.1152/ajprenal.00201.2005 -
The Journal of Clinical Investigation Dec 1974The intrarenal gradient of renin activity was determined in rats by using superficial (S) and deep (D) cortical juxtaglomerular apparatuses (JGA's), identified and... (Comparative Study)
Comparative Study
The intrarenal gradient of renin activity was determined in rats by using superficial (S) and deep (D) cortical juxtaglomerular apparatuses (JGA's), identified and microdissected after silicone-rubber compound injection. Angiotensin generated from single JGA's using partially purified sheep renin substrate was quantified by rat bioassay. When, in rats on a normal NaCl diet, silicone-rubber was injected into a carotid artery, alone or with abdominal aorta catheterization, S:D renin activity ratios were 1.18+/-0.08 (SEM) and 1.21+/-0.12, respectively. The S:D renin activity ratios obtained when silicone-rubber was injected into the abdominal aorta (2.52+/-0.09) or a chronic carotid artery catheter (3.44+/-0.40) were significantly higher (P < 0.001). The lower S:D renin activity ratios after carotid artery manipulation were due to significantly higher D-JGA renin activities. This increased D-JGA renin activity and the lack of a renin gradient appear to be related to acute carotid artery manipulation. Alterations in JGA renin activity were examined relative to NaCl intake. 2 wk after high-NaCl diet the absolute net renin activity decreased (P < 0.001) more in S (5.84+/-0.11 ng AI.JGA(-1).h(-1)) than D (1.73+/-0.06 ng AI.JGA(-1).h(-1)) JGA's, and the intrarenal renin gradient was lost (S:D-JGA renin activity, 1.00+/-0.07), as compared to the regular NaCl diet. 2 wk of a low-NaCl diet resulted in a greater (P < 0.01) increase in S (14.28+/-1.47 ng AI.JGA(-1).h(-1)) than D (9.62+/-1.19 ng AI.JGA(-1).h(-1)) JGA renin activity and a renin gradient (S:D-JGA renin activity) of 1.75+/-0.12. These results demonstrate that NaCl intake clearly influences total JGA renin content and may also affect the relative intrarenal distribution of renin activity.
Topics: Angiotensin II; Animals; Aorta, Abdominal; Biological Assay; Carotid Arteries; Catheterization; Diet; Diet, Sodium-Restricted; Dissection; Juxtaglomerular Apparatus; Male; Radioimmunoassay; Rats; Renin; Sheep; Sodium Chloride
PubMed: 4373493
DOI: 10.1172/JCI107884