Preservation of Intracellular Renin Expression Is Insufficient to Compensate for Genetic Loss of Secreted Renin

Xu, Di; Borges, Giulianna R.; Grobe, Justin L; Pelham, Christopher J.; Yang, Baoli

doi:10.1161/hypertensionaha.109.138677

Cited by 36 publications

(62 citation statements)

References 30 publications

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“…Consistent with a concept for coexpression of renin and AGT, angiotensin peptides were identified within cell bodies of the magnocellular parts of the SON and PVN, the cell bodies and fibers of the SFO, and the cell bodies of the BNST, CeA, and nucleus tractus solitarius (NTS) (81). The presence of intracellular angiotensin peptides is also consistent with molecular and functional evidence for the expression of a novel intracellular form of renin in the brain (74,125), although genetic analysis revealed that the intracellular form of renin cannot compensate for a loss of renal-derived secreted renin (146). These studies support the hypothesis for local activation of the RAS within the brain and data supporting the concept that ANG II is synthesized within the SFO and acts in the PVN as a neurotransmitter (35,78).…”

Section: Localization Of Ras Components Required For Ang II Productionmentioning

confidence: 65%

Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ

Coble¹,

Grobe

Johnson³

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Coble JP, Grobe JL, Johnson AK, Sigmund CD. Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ. Am J Physiol Regul Integr Comp Physiol 308: R238 -R249, 2015. First published December 17, 2014 doi:10.1152/ajpregu.00486.2014.-It is critical for cells to maintain a homeostatic balance of water and electrolytes because disturbances can disrupt cellular function, which can lead to profound effects on the physiology of an organism. Dehydration can be classified as either intra-or extracellular, and different mechanisms have developed to restore homeostasis in response to each. Whereas the renin-angiotensin system (RAS) is important for restoring homeostasis after dehydration, the pathways mediating the responses to intra-and extracellular dehydration may differ. Thirst responses mediated through the angiotensin type 1 receptor (AT 1R) and angiotensin type 2 receptors (AT 2R) respond to extracellular dehydration and intracellular dehydration, respectively. Intracellular signaling factors, such as protein kinase C (PKC), reactive oxygen species (ROS), and the mitogen-activated protein (MAP) kinase pathway, mediate the effects of central angiotensin II (ANG II). Experimental evidence also demonstrates the importance of the subfornical organ (SFO) in mediating some of the fluid intake effects of central ANG II. The purpose of this review is to highlight the importance of the SFO in mediating fluid intake responses to dehydration and ANG II.angiotensin; blood pressure; barin; fluid; renin FLUID BALANCE is crucial for the homeostasis and survival of organisms because they have to properly maintain fluid and electrolyte concentrations for the normal function of all cells. Fluid balance can go awry in pathological states such as in chronic kidney disease and diabetes. Among its many roles in maintaining homeostasis, the renin-angiotensin system (RAS) is an important regulator of fluid balance. The RAS achieves this through the actions of its main effector peptide, angiotensin II (ANG II) through the ANG II type 1 (AT 1 R) and type 2 (AT 2 R) receptors. Activation of AT 1 R by blood-borne ANG II in target tissues causes increases in sodium and water retention, arginine vasopressin (AVP), and aldosterone release, vasoconstriction, increased sympathetic nervous system activity, and increased fluid intake. ANG II is produced by the consecutive enzymatic action of renin on its substrate angiotensinogen (AGT) and by angiotensin-converting enzyme (ACE) on its substrate angiotensin I (ANG I). The renin-AGT cleavage step is generally the rate-limiting step in the production of ANG II, and this is certainly true in the brain where the amount of renin is limiting. The RAS exists in two forms: a circulatory form where ANG II acts as an endocrine factor, and a tissue-specific form, where local production of ANG II acts in an autocrine or paracrine manner to induce AT 1 R signaling on ANG II producing or nearby cells (75). Intracrine, or intracellular forms of the RAS, hav...

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Section: Localization Of Ras Components Required For Ang II Productionmentioning

confidence: 65%

Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ

Coble¹,

Grobe

Johnson³

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

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“…23 The mechanisms for the peculiar striped fibrosis remain to be studied, but it is likely to result from the combination of abnormal vessel architecture, which together with arterial hypotension leads to localized tissue hypoperfusion and ischemia along the path where the renal vessels traverse from the juxtamedullary area through the renal cortex ( Figure 7). 23 Contrary to the phenotype encoun- BRIEF REVIEW www.jasn.org tered in mice with targeted deletions of the renin angiotensin system genes, [17][18][19][20][21][22] in which SMCs proliferate around the blood vessel ( Figure 6), Dicer Ϫ/Ϫ animals do not have arteriolar thickening, displaying instead adventitial fibroplasia. 23 The reasons for the apparent decrease in SMCs is unlikely to be due to decreased renin because mice with homozygous deletion of the renin gene also have arteriolar thickening.…”

Section: Role Of Micrornas In Vascular Developmentmentioning

confidence: 98%

“…When this process fails, the consequences are devastating as exemplified by the serious developmental defects described below, which occur (particularly in the newborn period when branching is at its peak) in animals and humans with ablation of renin cell precursors, mutations of the renin-angiotensin system, and lack of microRNAs in the renal vasculature, resulting in early arterial and arteriolar abnormalities that are followed by deterioration of kidney structure and function. [15][16][17][18][19][20][21][22][23] In spite of its importance, very little is known about the fate of the vascular precursors and the mechanisms that lead them to differentiate and assemble into the kidney arterioles.…”

Section: Anatomical Development Of the Renal Arterial Treementioning

confidence: 99%

Development of the Renal Arterioles

López

Gómez

2011

Journal of the American Society of Nephrology

125

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“…In these mice, membrane-targeted Tomato (mT) is expressed in all the cells prior to Cre-mediated recombination, whereas membrane-targeted green fluorescent protein (mG) is expressed only in the cells undergoing Cre-expression and recombination. Thus, both R26R.LacZ and mT/mG Cre-reporter mice allow us to label cells (and all their descendants) permanently at the sites where Cre-recombination occurs, enabling lineage and fatetracing studies.Ren1 c flox/flox mice harbor the exon 1 of the renin gene flanked by loxP sites and its global deletion replicates the phenotype observed in the total Ren1 c KO mouse (31,32). To investigate the role of renin in vascular cells, we used FoxD1-GFP-Cre mice (10).…”

mentioning

confidence: 99%

Vascular versus tubular renin: role in kidney development

Sequeira-Lόpez

Nagalakshmi

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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-Renin, the key regulated enzyme of the renin-angiotensin system regulates blood pressure, fluid-electrolyte homeostasis, and renal morphogenesis. Whole body deletion of the renin gene results in severe morphological and functional derangements, including thickening of renal arterioles, hydronephrosis, and inability to concentrate the urine. Because renin is found in vascular and tubular cells, it has been impossible to discern the relative contribution of tubular versus vascular renin to such a complex phenotype. Therefore, we deleted renin independently in the vascular and tubular compartments by crossing Ren1 c fl/fl mice to Foxd1-cre and Hoxb7-cre mice, respectively. Deletion of renin in the vasculature resulted in neonatal mortality that could be rescued with daily injections of saline. The kidneys of surviving mice showed the absence of renin, hypertrophic arteries, hydronephrosis, and negligible levels of plasma renin. In contrast, lack of renin in the collecting ducts did not affect kidney morphology, intra-renal renin, or circulating renin in basal conditions or in response to a homeostatic stress, such as sodium depletion. We conclude that renin generated in the renal vasculature is fundamental for the development and integrity of the kidney, whereas renin in the collecting ducts is dispensable for normal kidney development and cannot compensate for the lack of renin in the vascular compartment. Further, the main source of circulating renin is the kidney vasculature.arterioles; conditional knockout; medulla; renin angiotensin system RENIN IS CRITICAL FOR THE control of blood pressure and fluid/ electrolyte homeostasis. In adult mammals, renin is synthesized and released from juxtaglomerular (JG) cells located in the wall of the afferent arterioles at the entrance to the glomeruli. However, within the embryonic (E) kidney, renin precursors appear before arteriolar development is discernible around E12.5-E14.5 days of gestation (22). JG cells descend from a group of stromal cells, which express the forkhead transcription factor Foxd1 and, in turn, differentiate into all the mural cells of the renal arterioles, pericytes, and glomerular mesangium (23). During this developmental process, renin cells regulate elongation and branching of the renal vasculature, where they are distributed broadly along large intrarenal arteries, in each tip of newly appearing arteriolar branches and inside glomerular cells, which differentiate into mesangial cells (7,8,18,21). Thus, during fetal and postnatal life, there is a widespread distribution and progressive shifting pattern of renin throughout the renal vasculature, and it is not until arteriolar development is finalized that these cells are circumscribed to their "classical" JG location, as typically seen in the adult mammal. Interestingly, Ren1 c KO mice display abnormal renal vascular development, with fewer, shorter, and prominently thicker renal interlobular arteries and afferent arterioles (28). In addition to the vascular abnormalities, the kidneys of Ren1 c KO ...

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Preservation of Intracellular Renin Expression Is Insufficient to Compensate for Genetic Loss of Secreted Renin

Cited by 36 publications

References 30 publications

Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ

Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ

Development of the Renal Arterioles

Vascular versus tubular renin: role in kidney development

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