Deciphering the Roles of Tissue Renin-Angiotensin Systems in Whole Animals

Reudelhuber, Timothy L.

doi:10.1161/hypertensionaha.110.167114

Cited by 7 publications

(3 citation statements)

References 29 publications

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“…The so-called extra-renal tissue RAS has been described in multiple organs, including the adrenal glands, heart, brain, vascular wall, reproductive tract, skin, digestive organs, sensory organs, and lymphatic tissue 42, 47, 48. Our findings suggest a role of pericytes in promoting extra-renal RAS.…”

Section: Discussionsupporting

confidence: 58%

Human kidney pericytes produce renin

Stefanska

Kenyon

Christian

et al. 2016

Kidney International

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Pericytes, perivascular cells embedded in the microvascular wall, are crucial for vascular homeostasis. These cells also play diverse roles in tissue development and regeneration as multi-lineage progenitors, immunomodulatory cells and as sources of trophic factors. Here, we establish that pericytes are renin producing cells in the human kidney. Renin was localized by immunohistochemistry in CD146 and NG2 expressing pericytes, surrounding juxtaglomerular and afferent arterioles. Similar to pericytes from other organs, CD146+CD34–CD45–CD56– renal fetal pericytes, sorted by flow cytometry, exhibited tri-lineage mesodermal differentiation potential in vitro. Additionally, renin expression was triggered in cultured kidney pericytes by cyclic AMP as confirmed by immuno-electron microscopy, and secretion of enzymatically functional renin, capable of generating angiotensin I. Pericytes derived from second trimester human placenta also expressed renin in an inducible fashion although the renin activity was much lower than in renal pericytes. Thus, our results confirm and extend the recently discovered developmental plasticity of microvascular pericytes, and may open new perspectives to the therapeutic regulation of the renin-angiotensin system.

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Section: Discussionsupporting

confidence: 58%

Human kidney pericytes produce renin

Stefanska

Kenyon

Christian

et al. 2016

Kidney International

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“…3 We found that the adenovirus was able to produce bioactive Ang II constitutively to the culture medium when it was infected in VSMCs. The functional assays further proved the usefulness of this tool to elucidate a relevant signaling mechanism of Ang II in vitro.…”

mentioning

confidence: 82%

Constitutive Stimulation of Vascular Smooth Muscle Cells by Angiotensin II Derived From an Adenovirus Encoding a Furin-Cleavable Fusion Protein

Takayanagi

Bourne

Kimura

et al. 2012

American Journal of Hypertension

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“…THE RENIN-ANGIOTENSIN SYSTEM (RAS) acts as a dual endocrine and local tissue paracrine system (1,6). There is increasing evidence that angiotensin (ANG) II may also function as an autocrine or intracrine peptide which exerts biological effects from within the cell without stimulating plasma membrane bound ANG II type 1 (AT 1 ) receptors (2,5).…”

mentioning

confidence: 99%

Trapping intracellular ANG II to the proximal tubule: powerful in vivo effects on sodium handling and blood pressure

Harrison‐Bernard

2011

American Journal of Physiology-Renal Physiology

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THE RENIN-ANGIOTENSIN SYSTEM (RAS) acts as a dual endocrine and local tissue paracrine system (1, 6). There is increasing evidence that angiotensin (ANG) II may also function as an autocrine or intracrine peptide which exerts biological effects from within the cell without stimulating plasma membrane bound ANG II type 1 (AT 1 ) receptors (2, 5). The autocrine or intracrine role of ANG II is not well understood, and the mechanisms by which intracellular ANG II exerts its physiological effects are unknown. Since the RAS serves as one of the most powerful regulators of arterial blood pressure by influencing sodium balance, extracellular fluid volume, and renal and systemic vascular resistance, there are multiple cell types in which intracellular ANG II may exert physiological effects. Intracellularly administered ANG II can induce biological effects which are inhibited by intracellular but not extracellular ANG II receptor blockade in vascular smooth muscle cells in vitro (3). However, the ability to distinguish the intracrine actions of ANG II in the physiological responses in an intact animal model had not been determined previously.In an issue of the American Journal of Physiology-Renal Physiology, the work of Li and colleagues (4) describes a novel approach to establishing the physiological significance of selective in vivo upregulation of intracellular ANG II in proximal tubule epithelial cells. The study was specifically designed to investigate the physiological effects of cytoplasmic ANG II-AT 1 receptor mediated effects on proximal tubule epithelial function. The unique contribution of this work is that the authors present convincing evidence for intracrine ANG II effects on sodium reabsorption and blood pressure using in vivo experimental approaches. Li et al. focused attention on the proximal tubule effects of intracellular ANG II since all of the major components of the RAS have been demonstrated in proximal tubule cells. An innovative methodology for targeting expression of ANG II to the proximal tubule was developed by the authors. They provide in vivo evidence that an adenoviral construct encoding a fluorescent fusion of ANG II linked to the enhanced cyan fluorescent protein (ECFP) which is driven by the sodium glucose cotransporter 2 (SGLT2) promoter can effectively deliver an intracellular fluorescent ANG II fusion protein selectively in proximal tubule cells. The adenoviral construct was injected into multiple renal cortical sites of rat and mouse kidneys and resulted in high proximal tubule expression for a period of up to 4 wk without evidence of secretion into the extracellular space. Since ECFP/ANG II is synthesized on free ribosomes and not destined for secretion out of the cells, ECFP/ANG II protein is thus trapped within the cytoplasm of the proximal tubule cell and is unable to act on cell surface AT 1 receptors. Confirmation of the expression pattern of ECFP/ANG II was performed by fluorescent immunohistochemical localization using CFP-and ANG II-specific antibodies to cortical proximal tub...

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Deciphering the Roles of Tissue Renin-Angiotensin Systems in Whole Animals

Cited by 7 publications

References 29 publications

Human kidney pericytes produce renin

Human kidney pericytes produce renin

Constitutive Stimulation of Vascular Smooth Muscle Cells by Angiotensin II Derived From an Adenovirus Encoding a Furin-Cleavable Fusion Protein

Trapping intracellular ANG II to the proximal tubule: powerful in vivo effects on sodium handling and blood pressure

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