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Kidney International Mar 2012The juxtaglomerular (JG) cell product renin is rate limiting in the generation of the bioactive octapeptide angiotensin II. Rates of synthesis and secretion of the... (Review)
Review
The juxtaglomerular (JG) cell product renin is rate limiting in the generation of the bioactive octapeptide angiotensin II. Rates of synthesis and secretion of the aspartyl protease renin by JG cells are controlled by multiple afferent and efferent pathways originating in the CNS, cardiovascular system, and kidneys, and making critical contributions to the maintenance of extracellular fluid volume and arterial blood pressure. Since both excesses and deficits of angiotensin II have deleterious effects, it is not surprising that control of renin is secured by a complex system of feedforward and feedback relationships. Mice with genetic alterations have contributed to a better understanding of the networks controlling renin synthesis and secretion. Essential input for the setting of basal renin generation rates is provided by β-adrenergic receptors acting through cyclic adenosine monophosphate, the primary intracellular activation mechanism for renin mRNA generation. Other major control mechanisms include COX-2 and nNOS affecting renin through PGE2, PGI2, and nitric oxide. Angiotensin II provides strong negative feedback inhibition of renin synthesis, largely an indirect effect mediated by baroreceptor and macula densa inputs. Adenosine appears to be a dominant factor in the inhibitory arms of the baroreceptor and macula densa mechanisms. Targeted gene mutations have also shed light on a number of novel aspects related to renin processing and the regulation of renin synthesis and secretion.
Topics: Animals; Animals, Genetically Modified; Connexins; Feedback, Physiological; Gene Expression Regulation; Genotype; Juxtaglomerular Apparatus; Mice; Mutation; Nitric Oxide Synthase; Phenotype; Prostaglandin-Endoperoxide Synthases; Receptors, Adrenergic; Receptors, Prostaglandin; Receptors, Purinergic P1; Renin; Renin-Angiotensin System; Signal Transduction
PubMed: 22258323
DOI: 10.1038/ki.2011.451 -
American Journal of Physiology. Renal... Jun 2005The highly inhomogeneous and light-scattering structure of living renal tissue makes the application of conventional imaging techniques more difficult compared with... (Review)
Review
The highly inhomogeneous and light-scattering structure of living renal tissue makes the application of conventional imaging techniques more difficult compared with other parenchymal organs. On the other hand, key physiological processes of the kidney, such as regulation of glomerular filtration, hemodynamics, concentration, and dilution, involve complex interactions between multiple cell types and otherwise inaccessible structures that necessitate visual approaches. An ideal solution is multiphoton excitation fluorescence microscopy, a state-of-the-art imaging technique superior for deep optical sectioning of living tissue samples. Here, we review the basics and advantages of multiphoton microscopy and provide examples for its application in renal physiology using dissected cortical and medullary tissues in vitro. In combination with microperfusion techniques, the major functions of the juxtaglomerular apparatus, tubuloglomerular feedback and renin release, can be studied with high spatial and temporal resolution. Salt-dependent changes in macula densa cell volume, vasoconstriction of the afferent arteriole, and activity of an intraglomerular precapillary sphincter composed of renin granular cells are visualized in real time. Release and tissue activity of renin can be studied on the individual granule level. Imaging of the living inner medulla shows how interstitial cells interconnect cells of the vasa recta, loop of Henle, and collecting duct. In summary, multiphoton microscopy is an exciting new optical sectioning technique that has great potential for numerous future developments and is ideal for applications that require deep optical sectioning of living tissue samples.
Topics: Animals; In Vitro Techniques; Kidney; Microscopy, Fluorescence, Multiphoton
PubMed: 15883166
DOI: 10.1152/ajprenal.00385.2004 -
Kidney International Dec 2010Diabetes mellitus is the most common and rapidly growing cause of end-stage renal disease. A classic hallmark of diabetes pathology is the activation of the intrarenal... (Review)
Review
Diabetes mellitus is the most common and rapidly growing cause of end-stage renal disease. A classic hallmark of diabetes pathology is the activation of the intrarenal renin-angiotensin system (RAS), which may lead to hypertension and renal tissue injury, but the mechanism of RAS activation has been elusive. Recently, we described the intrarenal localization of the novel metabolic receptor GPR91 and established some of its functions in diabetes. These include the triggering of renin release in early diabetes via both vascular (endothelial) and tubular (macula densa) sites in the juxtaglomerular apparatus as well as the activation of MAP kinases in the distal nephron-collecting duct, which are important signaling mechanisms in diabetic nephropathy (DN) and renal fibrosis. GPR91 is a cell surface receptor for succinate and during the past few years it has provided a new paradigm for the mechanism of cell stress response in many organs. Beyond its traditional role in the tricarboxylic acid cycle, succinate now has an unexpected hormone-like signaling function, which may provide a feedback between local tissue metabolism, mitochondrial stress, and organ functions. Succinate accumulation in the local tissue environment and GPR91 signaling appear to be important early mechanisms by which cells detect and respond to hyperglycemia and trigger tissue injury in DN. Also, the distal nephron-collecting duct system, which is the major source of (pro)renin in diabetes and has the highest level of GPR91 expression in the kidney, may have an important, active, and early role in the pathogenesis of DN in contrast to the existing glomerulus-centric paradigm.
Topics: Diabetic Nephropathies; Glomerular Filtration Rate; Humans; Hyperglycemia; Kidney Tubules, Distal; Receptors, G-Protein-Coupled; Renin; Signal Transduction; Succinic Acid
PubMed: 20861827
DOI: 10.1038/ki.2010.333 -
Kidney International. Supplement Sep 1998Recent work has provided substantial insights into functional characteristics of macula densa (MD) cells. Microelectrode and patch-clamp experiments on the rabbit... (Review)
Review
Recent work has provided substantial insights into functional characteristics of macula densa (MD) cells. Microelectrode and patch-clamp experiments on the rabbit isolated thick ascending limb (TAL)/glomerulus preparation have shown that MD cells possess a furosemide-sensitive Na:K:2Cl cotransporter, an apical 41-pS K+ channel, and a dominant basolateral Cl- conductance. Increasing luminal fluid [NaCl] ([NaCl]L) results in furosemide-sensitive cell depolarization due to a rise in intracellular [Cl-] that stimulates basolateral electrogenic Cl- efflux. Intracellular pH (pHi) measurements show the presence of an apical Na:H exchanger that couples transepithelial Na+ transport to pHi. Experimental results and thermodynamic considerations allow estimation of intracellular [Na+] and [Cl-] ([Na+]i, [Cl-]i) under different conditions. When the Na:K:2Cl cotransporter is equilibrated (or in the presence of furosemide), [Na+]i and [Cl-]i are low (approximately 6 to 7 mM), whereas when the cotransporter is fully activated, [Na+]i and [Cl-]i increase substantially to approximately 70 and 20 mM, respectively. Finally, luminal addition of NH4+ produces cell acidification that depends on NH4+ apical transport rate through the Na:K:2Cl. Using a simple transport model for NH4+, the initial NH4+ influx rate in MD cells is comparable to the corresponding flux in TAL. This challenges the idea that MD cells have a low transport activity but supports our findings about large changes in intracellular concentrations as a function of [NaCl]L.
Topics: Animals; Carrier Proteins; Chlorides; Juxtaglomerular Apparatus; Potassium; Sodium; Sodium-Potassium-Chloride Symporters
PubMed: 9736255
DOI: 10.1046/j.1523-1755.1998.06712.x -
Diagnostic Pathology Aug 2011Juxtaglomerular cell tumor (JGCT) generally affects adolescents and young adults. The patients experience symptoms related to hypertension and hypokalemia due to... (Review)
Review
Juxtaglomerular cell tumor (JGCT) generally affects adolescents and young adults. The patients experience symptoms related to hypertension and hypokalemia due to renin-secretion by the tumor. Grossly, the tumor is well circumscribed with fibrous capsule and the cut surface shows yellow or gray-tan color with frequent hemorrhage. Histologically, the tumor is composed of monotonous polygonal cells with entrapped normal tubules. Immunohistochemically, tumor cells exhibit a positive reactivity for renin, vimentin and CD34. Ultrastructurally, neoplastic cells contain rhomboid-shaped renin protogranules. Genetically, losses of chromosomes 9 and 11 were frequently observed. Clinically, the majority of tumors showed a benign course, but rare tumors with vascular invasion or metastasis were reported. JGCT is a curable cause of hypertensive disease if it is discovered early and surgically removed, but may cause a fatal outcome usually by a cerebrovascular attack or may cause fetal demise in pregnancy. Additionally, pathologists and urologists need to recognize that this neoplasm in most cases pursues a benign course, but aggressive forms may develop in some cases.
Topics: Diagnosis, Differential; Humans; Juxtaglomerular Apparatus; Kidney Neoplasms; Predictive Value of Tests; Prognosis
PubMed: 21871063
DOI: 10.1186/1746-1596-6-80 -
Journal of Biomedical Science Feb 2023Genome-wide association studies (GWASs) have linked RRBP1 (ribosomal-binding protein 1) genetic variants to atherosclerotic cardiovascular diseases and serum lipoprotein...
BACKGROUND
Genome-wide association studies (GWASs) have linked RRBP1 (ribosomal-binding protein 1) genetic variants to atherosclerotic cardiovascular diseases and serum lipoprotein levels. However, how RRBP1 regulates blood pressure is unknown.
METHODS
To identify genetic variants associated with blood pressure, we performed a genome-wide linkage analysis with regional fine mapping in the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) cohort. We further investigated the role of the RRBP1 gene using a transgenic mouse model and a human cell model.
RESULTS
In the SAPPHIRe cohort, we discovered that genetic variants of the RRBP1 gene were associated with blood pressure variation, which was confirmed by other GWASs for blood pressure. Rrbp1- knockout (KO) mice had lower blood pressure and were more likely to die suddenly from severe hyperkalemia caused by phenotypically hyporeninemic hypoaldosteronism than wild-type controls. The survival of Rrbp1-KO mice significantly decreased under high potassium intake due to lethal hyperkalemia-induced arrhythmia and persistent hypoaldosteronism, which could be rescued by fludrocortisone. An immunohistochemical study revealed renin accumulation in the juxtaglomerular cells of Rrbp1-KO mice. In the RRBP1-knockdown Calu-6 cells, a human renin-producing cell line, transmission electron and confocal microscopy revealed that renin was primarily retained in the endoplasmic reticulum and was unable to efficiently target the Golgi apparatus for secretion.
CONCLUSIONS
RRBP1 deficiency in mice caused hyporeninemic hypoaldosteronism, resulting in lower blood pressure, severe hyperkalemia, and sudden cardiac death. In juxtaglomerular cells, deficiency of RRBP1 reduced renin intracellular trafficking from ER to Golgi apparatus. RRBP1 is a brand-new regulator of blood pressure and potassium homeostasis discovered in this study.
Topics: Animals; Humans; Mice; Aldosterone; Aluminum Oxide; Blood Pressure; Genome-Wide Association Study; Homeostasis; Hyperkalemia; Hypertension; Hypoaldosteronism; Potassium; Renin; Carrier Proteins
PubMed: 36803854
DOI: 10.1186/s12929-023-00905-7 -
Kidney International. Supplement Sep 1998Cyclooxygenase (COX)-2 mRNA and immunoreactive protein localize to the macula densa and adjacent cortical thick ascending limb in renal cortex, and chronic NaCl... (Review)
Review
Cyclooxygenase (COX)-2 mRNA and immunoreactive protein localize to the macula densa and adjacent cortical thick ascending limb in renal cortex, and chronic NaCl restriction increases expression of this enzyme. These findings suggest an integral role for eicosanoids generated by macula densa-associated COX-2 in mediating renin release. As selective inhibitors of COX-2 become available, it will be important to assess their effects on the renin-angiotensin system and glomerular hemodynamics.
Topics: Animals; Cyclooxygenase 2; Isoenzymes; Juxtaglomerular Apparatus; Loop of Henle; Prostaglandin-Endoperoxide Synthases; Prostaglandins
PubMed: 9736253
DOI: 10.1046/j.1523-1755.1998.06710.x -
Current Hypertension Reports Feb 2017During development, renin cells are precursors for arteriolar smooth muscle, mesangial cells, and interstitial pericytes. Those seemingly differentiated descendants... (Review)
Review
During development, renin cells are precursors for arteriolar smooth muscle, mesangial cells, and interstitial pericytes. Those seemingly differentiated descendants retain the memory to re-express renin when there is a threat to homeostasis. Understanding how such molecular memory is constructed and regulated would be crucial to comprehend cell identity which is, in turn, intimately linked to homeostasis.
Topics: Animals; Cell Plasticity; Homeostasis; Humans; Juxtaglomerular Apparatus; Kidney; Renin
PubMed: 28233238
DOI: 10.1007/s11906-017-0711-8 -
American Journal of Physiology.... Nov 2000The sympathetic nervous system provides differentiated regulation of the functions of various organs. This differentiated regulation occurs via mechanisms that operate... (Review)
Review
The sympathetic nervous system provides differentiated regulation of the functions of various organs. This differentiated regulation occurs via mechanisms that operate at multiple sites within the classic reflex arc: peripherally at the level of afferent input stimuli to various reflex pathways, centrally at the level of interconnections between various central neuron pools, and peripherally at the level of efferent fibers targeted to various effectors within the organ. In the kidney, increased renal sympathetic nerve activity regulates the functions of the intrarenal effectors: the tubules, the blood vessels, and the juxtaglomerular granular cells. This enables a physiologically appropriate coordination between the circulatory, filtration, reabsorptive, excretory, and renin secretory contributions to overall renal function. Anatomically, each of these effectors has a dual pattern of innervation consisting of a specific and selective innervation by unmyelinated slowly conducting C-type renal sympathetic nerve fibers in addition to an innervation that is shared among all the effectors. This arrangement permits the maximum flexibility in the coordination of physiologically appropriate responses of the tubules, the blood vessels, and the juxtaglomerular granular cells to a variety of homeostatic requirements.
Topics: Animals; Humans; Juxtaglomerular Apparatus; Kidney; Nerve Fibers; Sympathetic Nervous System
PubMed: 11049831
DOI: 10.1152/ajpregu.2000.279.5.R1517 -
Journal of the American Society of... Mar 2009Absence of connexin 40 (Cx40) leads to ectopic juxtaglomerular renin expression and abrogates recruitment of renin-expressing cells in the adult kidney but does not...
Absence of connexin 40 (Cx40) leads to ectopic juxtaglomerular renin expression and abrogates recruitment of renin-expressing cells in the adult kidney but does not disturb renin expression during kidney development. To find an explanation for these observations, we aimed to analyze the expression pattern of major vascular Cxs in normal juxtaglomerular epithelioid cells, in recruited renin-expressing cells, and in fetal renin-expressing cells. We found that during kidney development, the appearance of renin-producing cells paralleled the expression of Cx40 and, to a lesser extent, Cx45 but not other Cxs. In the adult kidney, juxtaglomerular epithelioid cells expressed Cx40 and lesser amounts of Cx37 and Cx43 but not Cx45, which localized to arteriolar smooth muscle cells. Recruitment of renin-producing cells in adult kidneys in response to long-term salt deprivation of mice correlated with the reappearance of only Cx40. Cx40-null renin-producing cells did not express Cx37, Cx43, or Cx45. These findings suggest that Cx40 expression is a characteristic of renin-producing cells in the kidney, and it seems to be essential in the recruitment of renin-producing cells in the adult but not the fetal kidney.
Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Connexin 43; Connexins; Diet, Sodium-Restricted; Enalapril; Fetus; Gap Junctions; Juxtaglomerular Apparatus; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Renin; Gap Junction alpha-5 Protein; Gap Junction alpha-4 Protein
PubMed: 19073828
DOI: 10.1681/ASN.2008030252