Functional Intracellular Renin-Angiotensin Systems May Exist in Multiple Tissues

Abstract

The r e n i n -a n g i o t e n s i n system is c u s t o m a r i l y thought o f as a h o m e o s t a t i c feedback l o o p i n v o l v e d i n t h e r e g u l a t i o n o f i n t r av a s c u l a r volume and p r e s s u r e . However, o v e r t h e l a s t t h r e e d e c a d e s , r e n i n h a s been i d e n t i f i e d i n a wide v a r i e t y o f n o n r e n a l t i s s u e s and indeed o u r l a b o r a t o r y h a s confirmed s y n t h e s i s o f r e n i n i n a t l e a s t one e x t r a r e n a l s i t e , namely, t h e a r t e r i a l smooth muscle c e l l ( 1 ) . Although an i m p o r t a n t n e u r o r e g u l a t o r y r o l e f o r angioprovided e v i d e n c e s u g g e s t i n g a d i r e c t effect o f a n g i o t e n s i n I1 on RNA polymerase I1 a c t i v i t y ( 4 ) a s well a s on c o n f o r m a t i o n a l changes i n chromatin o f t h e s o r t a s s o c i a t e d w i t h enhanced t r a n s c r i p t i o n ( 5 , 6 1. A l l t h e s e o b s e r v a t i o n s s u g g e s t t h a t t h e i n t r a c e l l u l a r s y n t h e s i s o f r e n i n may b e d i r e c t e d toward t h e i n t r a c e l l u l a r s y n t h e s i s o f a n g i o t e n s i n I1 and subsequent e f f e c t s on i n t r a c e l l u l a r homeostasis. W e now e x t e n d t h e s e o b s e r v a t i o n s . MATERIALS AND METHODS I s o l a t i o n o f N u c l e i , Nuclease D i g e s t i o n and F r a c t i o n a t i o n o f Chromatin. P r o c e d u r e s have been p r e v i o u s l y d e s c r i b e d ( 5 , 6 ) . N u c l e i were o b t a i n e d from e i t h e r rat l i v e r o r bovine thymus as i n d i c a t e d under r e s u l t s . Hormone I n c u b a t i o n : Washed n u c l e a r p e l l e t o b t a i n e d from r a t l i v e r o r bovine thymus w a s suspended i n hormone i n c u b a t i o n b u f f e r (150 mM N a C 1 , 10 mM T r i s , 5 mM DTT, 1 mM PMSF, pH 7.5) @ tvgj d e s i r e d conc e n t r a t i o n p r i o r t o t h e a d d i t i o n o f e i t h e r

Implications of intracrine hormone action for physiology and medicine

“…Collectively, these findings suggest the existence of intracrine angiotensin action and also again raise the possibility that a complete iRAS exists in some cells (53). An additional point can be made.…”

“…Nuclear angiotensin receptors were subsequently reported to be At-1-like in that they were blocked by losartan, and these reports showed receptors were present in association with both the nuclear membrane and, again, with chromatin. Confirmation that binding of angiotensin to isolated nuclei resulted in increased gene transcription was later provided by the observation that nuclear angiotensin upregulates renin, angiotensinogen, and platelet-derived growth factor (PDGF) transcription (9,10,12,47,48,(50)(51)(52)(53). Moreover, electron microscopic immunohistochemical techniques were used to demonstrate angiotensin II immunoreactivity located in association with the euchromatin of cerebellar neurons, hepatocytes, and adrenal cells from normal animals (13).…”

“…One is then lead to ask whether the RAS could also operate in the intracellular arena; i.e., in an intracrine mode (iRAS). More than three decades ago it was reported (47,48,(50)(51)(52)(53) that labeled angiotensin trafficked from the circulation and localized to cardiac myocyte nuclei and to mitochondria. Ten years later, our group (47) reported specific angiotensin receptors in isolated nuclei and associated with chromatin; angiotensin binding to those receptors increased gene transcription.…”

“…Over the last three decades evidence has accumulated to indicate that at least some peptide hormones and growth factors also bind and act in the cellular interior either after internalization by target cells or retention in their cells of synthesis . Several years ago our laboratory (48,53) proposed the term intracrine for such intracellularly acting peptides hormones irrespective of whether their binding/action followed internalization or occurred in the cell that synthesized them. In fact, many intracrines act in both fashions.…”

Intracellular Renin and the Nature of Intracrine Enzymes

“…14 -26 Years ago, we applied the term intracrine to the intracellular action of a peptidic factor/hormone irrespective of whether the factor (or isoform) was internalized by its target cell before acting or was retained in its cell of synthesis to act. 14,15 A list of representative intracrines is found in the Table. The biology of these factors as well as our suggestions regarding their origins and mechanisms of action are discussed in depth elsewhere. 1,2,16 -19,23-26 Against this background, we will concern ourselves with the following questions: (1) Is the prorenin/renin molecule an intracrine?…”