The intracellular renin–angiotensin system: a new paradigm

doi:10.1016/j.tem.2007.05.001

Trends in Endocrinology & Metabolism

Volume 18, Issue 5, July 2007, Pages 208-214

https://doi.org/10.1016/j.tem.2007.05.001 Get rights and content

More than a century after its discovery, the physiological implications of the renin–angiotensin system (RAS) continue to expand, with the identification of new components, functions and subsystems. These advancements have led to better management and understanding of a broad range of cardiovascular and metabolic disorders. The RAS has traditionally been viewed as a circulatory system, involved in the short-term regulation of volume and blood pressure homeostasis. Recently, local RASs have been described as regulators of chronic tissue effects. Most recently, studies have provided evidence of a complete, functional RAS within cells, described as an ‘intracrine’ or intracellular system. A more comprehensive understanding of the intracellular RAS provides for new strategies in system regulation and a more efficacious approach to the management of RAS-related diseases.

Section snippets

Introduction: the renin–angiotensin system

There has been significant advancement in knowledge regarding the renin–angiotensin system (RAS) over the past several decades. Originally, the RAS was viewed as consisting of a single, biologically active hormone angiotensin II (Ang II), generated by the sequential action of renin on angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) on the cleaved product from AGT, angiotensin I (Ang I) [1]. Ang II interacts with two well-characterized plasma membrane receptors, AT₁ and AT₂, and

Classical RAS

The classical RAS is systemic in nature, whereby Ang II is synthesized in the circulation and contributes to maintaining electrolyte balance, body fluid volume and arterial pressure primarily through vasoconstriction and aldosterone production. One of the most significant advancements in the past two decades has been the discovery of local or tissue RASs 8, 9. A local system is characterized by the presence of RAS components, AGT and the conversion enzymes, local synthesis of Ang II, and

Intracellular RAS

Similar to the classification of the RAS into systemic or local systems, which were defined by circulatory or tissue synthesis of Ang II, the intracellular RAS is characterized by the presence of its components inside the cell and synthesis of Ang II at an intracellular site. The primary nature of RAS components, such as the presence of signal peptides in AGT and renin, and the transmembrane nature of ACE, is generally thought not to be supportive of an intracellular system. However, the

Components of the intracellular RAS

The intracellular RAS includes the following components: AGT, renin, ACE, chymase and various receptors.

Intracellular synthesis of Ang II

Several studies have provided evidence for intracellular generation of Ang II in cultured kidney and heart cells and in the intact heart.

Functions of the intracellular RAS

The earliest study suggesting functional effects of intracellular Ang II date back to 1971, when Robertson and Khairallah [7] demonstrated localization of injected Ang II in the nuclei of smooth and cardiac muscle cells, accompanied by ultrastructural cellular changes. Later, Re et al. 40, 44 demonstrated Ang II binding sites in chromatin fragments that resulted in increased RNA synthesis by Ang II. The coupling of nuclear membrane Ang II receptors to increased transcription of the genes

Mechanism of action of intracellular Ang II

The effects of intracellular Ang II are varied, ranging from Ca²⁺ modulation, to cell growth and gene expression. Whereas extracellular Ang II induces both Ca²⁺ influx and release from intracellular stores, the effects of intracellular Ang II seem to vary among cell types. In rat aortic VSMCs, the increase in [Ca²⁺]_i resulted from an influx of extracellular Ca²⁺ [65]. Likewise, the intracellular Ang II-induced contraction of rat aorta rings was dependent on Ca²⁺ influx, not on inositol

Significance of the intracellular RAS

Several studies have demonstrated the existence of a functional intracellular RAS 76, 77; however, the physiological and pathophysiological role of this system remains to be determined. Is the intracellular RAS a general phenomenon or is it restricted to specific tissues, cells or pathophysiological conditions? The effects of intracellular Ang II in a variety of cells, namely cardiac [71], renal [73], hepatic [69] and vascular 45, 78 cells, suggests a broad relevance of the system.

Conclusion

In summary, there is increasing evidence, both direct and indirect, in support of the existence of a complete and functional intracellular RAS in multiple tissues. The intracellular RAS probably does not represent an independent entity but an extension or alternative form of a local RAS, which might be manifested only under select pathophysiological conditions, such as hyperglycemia. This suggests a unique evolutionary role of the intracellular RAS. What remain to be determined are the

References (87)

M. Kurdi
Working outside the system: an update on the unconventional behavior of the renin-angiotensin system components
Int. J. Biochem. Cell Biol.
(2005)
M. Bader
Role of the local renin-angiotensin system in cardiac damage: a minireview focussing on transgenic animal models
J. Mol. Cell. Cardiol.
(2002)
J. Varagic et al.
Local cardiac renin-angiotensin system: hypertension and cardiac failure
J. Mol. Cell. Cardiol.
(2002)
A.P. Gimenez-Roqueplo
Role of N-glycosylation in human angiotensinogen
J. Biol. Chem.
(1998)
M. Miyazaki et al.
Tissue angiotensin II generating system by angiotensin-converting enzyme and chymase
J. Pharmacol. Sci.
(2006)
G. von Heijne
The efficiency of the uncleaved secretion signal in the plasminogen activator inhibitor type 2 protein can be enhanced by point mutations that increase its hydrophobicity
J. Biol. Chem.
(1991)
A.P. Gimenez-Roqueplo
The natural mutation Y248C of human angiotensinogen leads to abnormal glycosylation and altered immunological recognition of the protein
J. Biol. Chem.
(1996)
T. Nakajima
Functional analysis of a mutation occurring between the two in-frame AUG codons of human angiotensinogen
J. Biol. Chem.
(1999)
R.N. Re
Angiotensin II receptors in chromatin fragments generated by micrococcal nuclease
Biochem. Biophys. Res. Commun.
(1984)
R. Re et al.
Effect of angiotensin II on RNA synthesis by isolated nuclei
Life Sci.
(1984)

J.L. Cook

Nuclear accumulation of the AT1 receptor in a rat vascular smooth muscle cell line: effects upon signal transduction and cellular proliferation

J. Mol. Cell. Cardiol.

(2006)

J.L. Cook

Intracellular angiotensin II fusion protein alters AT1 receptor fusion protein distribution and activates CREB

J. Mol. Cell. Cardiol.

(2004)

N. Sugiura

Molecular cloning of porcine soluble angiotensin-binding protein

J. Biol. Chem.

(1992)

M.A. Kiron et al.

Purification and properties of a soluble angiotensin II-binding protein from rabbit liver

J. Biol. Chem.

(1989)

V.T. Karamyan et al.

Identification of a novel non-AT1, non-AT2 angiotensin binding site in the rat brain

Brain Res.

(2007)

C. Mercure

Evidence for intracellular generation of angiotensin II in rat juxtaglomerular cells

FEBS Lett.

(1998)

K. Jandeleit-Dahm et al.

Hypertension and diabetes: role of the renin-angiotensin system

Endocrinol. Metab. Clin. North Am.

(2006)

W.C. De Mello

Further studies on the effect of intracellular angiotensins on heart cell communication: on the role of endogenous angiotensin II

Regul. Pept.

(2003)

K.M. Baker

Evidence of a novel intracrine mechanism in angiotensin II-induced cardiac hypertrophy

Regul. Pept.

(2004)

C.M. Filipeanu

Intracellular angiotensin II elicits Ca2+ increases in A7r5 vascular smooth muscle cells

Eur. J. Pharmacol.

(2001)

C.M. Filipeanu

Intracellular angiotensin II inhibits heterologous receptor stimulated Ca2+ entry

Life Sci.

(2001)

W.C. De Mello

Cardiac intracrine renin angiotensin system. Part of genetic reprogramming?

Regul. Pept.

(2006)

R.N. Re et al.

The intracrine hypothesis: an update

Regul. Pept.

(2006)

F. Fiordaliso

Myocyte death in streptozotocin-induced diabetes in rats in angiotensin II- dependent

Lab. Invest.

(2000)

R.M. Carey et al.

The intrarenal renin-angiotensin system and diabetic nephropathy

Trends Endocrinol. Metab.

(2003)

J.E. Hall

Historical perspective of the renin-angiotensin system

Mol. Biotechnol.

(2003)

M. de Gasparo

International union of pharmacology. XXIII. The angiotensin II receptors

Pharmacol. Rev.

(2000)

L. Hunyady et al.

Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II

Mol. Endocrinol.

(2006)

R.M. Carey et al.

Newly recognized components of the renin-angiotensin system: potential roles in cardiovascular and renal regulation

Endocr. Rev.

(2003)

M.C. Chappell

Novel aspects of the renal renin-angiotensin system: angiotensin-(1-7), ACE2 and blood pressure regulation

Contrib. Nephrol.

(2004)

A.L. Robertson et al.

Angiotensin II: rapid localization in nuclei of smooth and cardiac muscle

Science

(1971)

M. Paul

Physiology of local renin-angiotensin systems

Physiol. Rev.

(2006)

R.N. Re

Mechanisms of disease: local renin-angiotensin-aldosterone systems and the pathogenesis and treatment of cardiovascular disease

Nat. Clin. Pract. Cardiovasc. Med.

(2004)

A.H. Danser

Local renin-angiotensin systems: the unanswered questions

Int. J. Biochem. Cell Biol.

(2003)

H. Haller

Spotlight on renin: intrarenal renin-angiotensin system – important player of the local milieu

J. Renin Angiotensin Aldosterone Syst.

(2006)

K. Sakai et al.

Molecular evidence of tissue renin-angiotensin systems: a focus on the brain

Curr. Hypertens. Rep.

(2005)

P.S. Leung et al.

Pancreatic islet renin angiotensin system: its novel roles in islet function and in diabetes mellitus

Pancreas

(2005)

G.H. Goossens

Endocrine role of the renin-angiotensin system in human adipose tissue and muscle: effect of beta-adrenergic stimulation

Hypertension

(2007)

M. Sherrod

Nuclear localization of angiotensinogen in astrocytes

Am. J. Physiol. Regul. Integr. Comp. Physiol.

(2004)

J.L. Lavoie

Evidence supporting a functional role for intracellular renin in the brain

Hypertension

(2006)

S. Clausmeyer

Tissue-specific expression of a rat renin transcript lacking the coding sequence for the prefragment and its stimulation by myocardial infarction

Endocrinology

(2000)

M.C. Camargo de Andrade

Expression and localization of N-domain ANG I-converting enzymes in mesangial cells in culture from spontaneously hypertensive rats

Am. J. Physiol. Renal Physiol.

(2006)

L.A. Belova

Angiotensin II-generating enzymes

Biochemistry (Mosc.)

(2000)

Cited by (106)

Increased CaMKII activation and contrast changes of cardiac β1-and β3-Adrenergic signaling pathways in a humanized angiotensinogen model of hypertension
2023, Heliyon
Upregulation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) contributes to the pathogenesis of cardiovascular disease, including hypertension. Transgenic rats expressing the human angiotensinogen gene [TGR (hAGT)L1623] are a new novel humanized model of hypertension that associates with declines in cardiac contractile function and β-adrenergic receptor (AR) reserve. The molecular mechanisms are unclear. We tested the hypothesis that in TGR (hAGT)L1623 rats, left ventricular (LV) myocyte CaMKIIδ and β₃-AR are upregulated, but β₁-AR is down-regulated, which are important causes of cardiac dysfunction and β-AR desensitization.
We compared LV myocyte CaMKIIδ, CaMKIIδ phosphorylation (at Thr287) (pCaMKIIδ), and β₁-and β₃-AR expressions and determined myocyte functional and [Ca²⁺]_I transient ([Ca²⁺]_iT) responses to β-AR stimulation with and without pretreatment of myocytes using an inhibitor of CaMKII, KN-93 (10⁻⁶ M, 30 min) in male Sprague Dawley (SD; N = 10) control and TGR (hAGT)L1623 (N = 10) adult rats.
Hypertension in TGR (hAGT)L1623 rats was accompanied by significantly increased LV myocyte β₃-AR protein levels and reduced β₁-AR protein levels. CaMKIIδ phosphorylation (at Thr287), pCaMKIIδ was significantly increased by 35%. These changes were followed by significantly reduced basal cell contraction (dL/dt_max), relaxation (dR/dt_max), and [Ca²⁺]_iT. Isoproterenol (10⁻⁸ M) produced significantly smaller increases in dL/dt_max, dR/dt_max, and [Ca²⁺]_iT. Moreover, only in TGR (hAGT)L1623 rats, pretreatment of LV myocytes with KN-93 (10⁻⁶ M, 30 min) fully restored normal basal and isoproterenol-stimulated myocyte contraction, relaxation, and [Ca²⁺]_iT.
LV myocyte CaMKIIδ overactivation with associated contrast changes in β₃-AR and β₁-AR may be the key molecular mechanism for the abnormal contractile phenotype and β-AR desensitization in this humanized model of hypertension.
Pannexin 1 channels in renin-expressing cells influence renin secretion and blood pressure homeostasis
2020, Kidney International
Kidney function and blood pressure homeostasis are regulated by purinergic signaling mechanisms. These autocrine/paracrine signaling pathways are initiated by the release of cellular ATP, which influences kidney hemodynamics and steady-state renin secretion from juxtaglomerular cells. However, the mechanism responsible for ATP release that supports tonic inputs to juxtaglomerular cells and regulates renin secretion remains unclear. Pannexin 1 (Panx1) channels localize to both afferent arterioles and juxtaglomerular cells and provide a transmembrane conduit for ATP release and ion permeability in the kidney and the vasculature. We hypothesized that Panx1 channels in renin-expressing cells regulate renin secretion in vivo. Using a renin cell-specific Panx1 knockout model, we found that male Panx1 deficient mice exhibiting a heightened activation of the renin-angiotensin-aldosterone system have markedly increased plasma renin and aldosterone concentrations, and elevated mean arterial pressure with altered peripheral hemodynamics. Following ovariectomy, female mice mirrored the male phenotype. Furthermore, constitutive Panx1 channel activity was observed in As4.1 renin-secreting cells, whereby Panx1 knockdown reduced extracellular ATP accumulation, lowered basal intracellular calcium concentrations and recapitulated a hyper-secretory renin phenotype. Moreover, in response to stress stimuli that lower blood pressure, Panx1-deficient mice exhibited aberrant “renin recruitment” as evidenced by reactivation of renin expression in pre-glomerular arteriolar smooth muscle cells. Thus, renin-cell Panx1 channels suppress renin secretion and influence adaptive renin responses when blood pressure homeostasis is threatened.
Renin angiotensin aldosterone inhibition in the treatment of cardiovascular disease
2017, Pharmacological Research
A collective century of discoveries establishes the importance of the renin angiotensin aldosterone system in maintaining blood pressure, fluid volume and electrolyte homeostasis via autocrine, paracrine and endocrine signaling. While research continues to yield new functions of angiotensin II and angiotensin-(1–7), the gap between basic research and clinical application of these new findings is widening. As data accumulates on the efficacy of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers as drugs of fundamental importance in the treatment of cardiovascular and renal disorders, it is becoming apparent that the achieved clinical benefits is suboptimal and surprisingly no different than what can be achieved with other therapeutic interventions. We discuss this issue and summarize new pathways and mechanisms effecting the synthesis and actions of angiotensin II. The presence of renin-independent non-canonical pathways for angiotensin II production are largely unaffected by agents inhibiting renin angiotensin system activity. Hence, new efforts should be directed to develop drugs that can effectively block the synthesis and/or action of intracellular angiotensin II. Improved drug penetration into cardiac or renal sites of disease, inhibiting chymase the primary angiotensin II forming enzyme in the human heart, and/or inhibiting angiotensinogen synthesis would all be more effective strategies to inhibit the system. Additionally, given the role of angiotensin II in the maintenance of renal homeostatic mechanisms, any new inhibitor should possess greater selectivity of targeting pathogenic angiotensin II signaling processes and thereby limit inappropriate inhibition.
The Renin–Angiotensin System and the Heart
2017, Textbook of Nephro-Endocrinology
The existence and physiological importance of the cardiac renin–angiotensin system has shaped the ways in which cardiovascular diseases are currently treated. The actions of two bioactive peptides of the RAS—angiotensin II and angiotensin-(1-7)—on the heart are opposing, which provides the system with a counterbalancing mechanism that may be altered in pathological states such as hypertension and heart disease. The current pharmacologic therapies for hypertension and heart failure, which include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, may act not only in the systemic circulation, but they may also act at local tissue sites, including the heart, to correct the imbalance of these two angiotensin peptides. This chapter encompasses a brief review of current literature as it pertains to the renin–angiotensin system in the heart and incorporates how current therapies are working toward treatment of cardiac disorders and heart failure.
Angiotensin ii therapy in refractory septic shock: which patient can benefit most? A narrative review
2024, Journal of Anesthesia, Analgesia and Critical Care
Prolylcarboxypeptidase Alleviates Hypertensive Cardiac Remodeling by Regulating Myocardial Tissue Angiotensin II
2023, Journal of the American Heart Association

View all citing articles on Scopus

View full text

Trends in Endocrinology & Metabolism

ReviewThe intracellular renin–angiotensin system: a new paradigm

Section snippets

Introduction: the renin–angiotensin system

Classical RAS

Intracellular RAS

Components of the intracellular RAS

Intracellular synthesis of Ang II

Functions of the intracellular RAS

Mechanism of action of intracellular Ang II

Significance of the intracellular RAS

Conclusion

Int. J. Biochem. Cell Biol.

J. Mol. Cell. Cardiol.

J. Mol. Cell. Cardiol.

J. Biol. Chem.

J. Pharmacol. Sci.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Life Sci.

J. Mol. Cell. Cardiol.

J. Mol. Cell. Cardiol.

J. Biol. Chem.

J. Biol. Chem.

Brain Res.

FEBS Lett.

Endocrinol. Metab. Clin. North Am.

Regul. Pept.

Regul. Pept.

Eur. J. Pharmacol.

Life Sci.

Regul. Pept.

Regul. Pept.

Lab. Invest.

Trends Endocrinol. Metab.

Historical perspective of the renin-angiotensin system

Mol. Biotechnol.

International union of pharmacology. XXIII. The angiotensin II receptors

Pharmacol. Rev.

Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II

Mol. Endocrinol.

Newly recognized components of the renin-angiotensin system: potential roles in cardiovascular and renal regulation

Endocr. Rev.

Novel aspects of the renal renin-angiotensin system: angiotensin-(1-7), ACE2 and blood pressure regulation

Contrib. Nephrol.

Angiotensin II: rapid localization in nuclei of smooth and cardiac muscle

Science

Physiology of local renin-angiotensin systems

Physiol. Rev.

Mechanisms of disease: local renin-angiotensin-aldosterone systems and the pathogenesis and treatment of cardiovascular disease

Nat. Clin. Pract. Cardiovasc. Med.

Local renin-angiotensin systems: the unanswered questions

Int. J. Biochem. Cell Biol.

Spotlight on renin: intrarenal renin-angiotensin system – important player of the local milieu

J. Renin Angiotensin Aldosterone Syst.

Molecular evidence of tissue renin-angiotensin systems: a focus on the brain

Curr. Hypertens. Rep.

Pancreatic islet renin angiotensin system: its novel roles in islet function and in diabetes mellitus

Pancreas

Endocrine role of the renin-angiotensin system in human adipose tissue and muscle: effect of beta-adrenergic stimulation

Hypertension

Nuclear localization of angiotensinogen in astrocytes

Am. J. Physiol. Regul. Integr. Comp. Physiol.

Evidence supporting a functional role for intracellular renin in the brain

Hypertension

Tissue-specific expression of a rat renin transcript lacking the coding sequence for the prefragment and its stimulation by myocardial infarction

Endocrinology

Expression and localization of N-domain ANG I-converting enzymes in mesangial cells in culture from spontaneously hypertensive rats

Am. J. Physiol. Renal Physiol.

Angiotensin II-generating enzymes

Biochemistry (Mosc.)

Review
The intracellular renin–angiotensin system: a new paradigm