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The renin angiotensin system plays an important role on the regulation of arterial pressure, blood volume and cardiac function. Both a circulating and several tissue-localized systems have been identified and able to cleave angiotensinogen by renin to form angiotensin I which is converted to angiotensin II (Ang II) by angiotensin converting enzyme. The presence of local Ang II generation, which has been supported by the beneficial effects of Ang II AT1 receptor blockers and ACE inhibitors independently of their effects on arterial blood pressure, certainly requires that renin, angiotensinogen and ACE be synthesized locally or taken from the plasma. Concerning the presence of the different components of the RAS in different tissues1 evidence is available that in nephrectomized rats, the renin levels in the heart, for instance, are extremely low2 what indicates that intracellular renin in cardiac myocytes of normal animals, would need to come from plasma. However, rats transgenic for the mouse ren-2 renin gene develop severe hypertension and cardiac remodeling3 and incubation of cardiac myocytes from these animals with prorenin (the precursor of renin) leads to intracellular appearance of angiotensin I and II3 what suggests prorenin internalization. Moreover, an alternative transcript for a nonsecreted renin has been described in brain and heart.4,5 The transfection of a nonsecreted form of angiotensinogen into hepatoma cells that expressed this renin transcript, increased proliferation by a process that is sensitive to renin antisense,6 indicating that the renin transcript has functional properties. Indeed, the alternative renin trancript is upregulated in adult rats with MI suggesting its contribution to intracellular Ang II generation under pathological conditions.7 Regardless of whether intracellular renin or Ang II is the result of intracellular synthesis or internalization, evidence exists that intracellular renin is able to increment the inward calcium current in myocytes from the failing heart.8 In addition, transgenic overexpression of the intracellular nonsecreted form of renin and angiotensinogen in the brain leads to an increase in drinking volume and mean arterial pressure.9 The work of Schefe et al10 indicated that the primary localization of the human renin/prorenin receptor (RER) is in the perinuclear zone what conflicts with previous studies indicating its localization in the plasma cell membrane.11 The intracellular localization was confirmed using different constructs and studies of mutagenesis and colocalization. Indeed, mutagenesis of the atypical C-terminal ER-retention signal strongly reduced the perinuclear localization of the renin receptor.10 Furthermore, a transcription factor promyelocytic zinc finger protein (PLZF) was identified as a direct protein interaction partner of the C-terminal domain of the renin receptor and following the activation of RER by renin, PLZF is translocated from the cytoplasm to the nucleus providing positive or negative regulation of target genes.10 Renin stimulation also increased PI3-K-85 messenger RNA whereas small interfering RNA against PLZF abolished this effect10. Moreover, experiments performed on PLZF knockout mice supported the view that PLZF is an upstream regulator of RER10. Interestingly, renin stimulation in rat H9c2 cardiomyoblasts not only increased the cell number but elicited a decrease of apoptosis.10 Although further studies will be needed to rule out the existence of more than 1 renin receptor, Schefe et al10 did not rule out the possibility that very small amount of RER within the plasma cell membrane might be sufficient to initiate a RER signal transduction cascade despite its intracellular localization. In this case, other receptors like mannose-6 phosphate receptors could internalize renin and prorenin12 and the intracellular Ang II formation elicited by renin internalization, might explain the severe cardiac damage seen in transgenic rats expressing the mouse ren-2 renin gene.13 The question remains whether renin is able to work by itself or depends on the formation of Ang II. Tissue accumulation of plasma prorenin results in angiotensin generation14 but could also, through binding to a recently cloned prorenin/renin receptor, lead to angiotensin-independent effects including p42/p44 mitogen-activated protein kinase (MAPK) activation and plasminogen-activator inhibitor (PAI-1) release15. In mesangial cells, renin increases transforming growth factor1 and matrix proteins also independently of Ang II mechanisms16 whereas in cardiomyocytes isolated from the failing heart, intracellular renin increments the inward calcium current, an effect suppressed by intracellular losartan.8 These apparent discrepant results lead us to think that the activation of RER has multiple functions some related to the activation of the RAS and other not (see Figure). Here caution must be exercised because variations of species or type of preparations used in the experiments might influence the results. The intracellular localization of the renin receptor described in Schefe’s article10 certainly reactivates the tantalized question whether an intracellular renin angiotensin system is involved on the regulation of tissue function in different pathophysiological conditions. Activation of this receptor by enhanced expression of renin gene elicited by cell stretch17 for instance, might be in part responsible for cardiac remodeling and changes in electrical properties.23,1 On the other hand, increased internalization of The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan. Correspondence to Walmor C. De Mello, Medical Sciences Campus, School of Medicine, PO Box 36–5067, San Juan, PR 00936-5067, USA. E-mail wmello@rcm.upr.edu (Circ Res. 2006;99:1285–1286.) © 2006 American Heart Association, Inc.

On the Pathophysiological Implications of an Intracellular Renin Receptor