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Tissue prorenin-renin-angiotensin systems: local regulatory roles in reproductive and endocrine organs
ELSEVIER
Regulatory Pept~des 53 (1994) 133-135
Introductory comments
Tissue prorenin-renin-angiotensin systems: local regulatory roles in reproductive and endocrine organs Areal K Mukhopadhyay* Hamburg Germam, Jufi 15-16 1994 A Satelhte S~mpo~tum to the IH European Endocrinology, Congress Amsterdam The Netherland~
In 1898, nearly a century ago, renln was discovered by Tlgerstedt and Bergman [ 1] During the most of the subsequent period, the renln-anglotensln system has been considered to be primarily a mixed enzymehormonal mechanism for the regulation of cardiovascular homeostasis But, during the last decade, important advances in two areas have revealed new facets in renan-anglotensln research One was the synthesis of a number of non-peptlde anglotensln II receptor antagonists and the other was an understanding of the molecular biology of the renlnanglotensln system The avallablhty of non-peptlde receptor antagonists and of molecular biology tools have made it possible now to determine the molecular pharmacology of a number of types and subtypes of anglotensln receptors [2,3] The cloning of the mammahan ATlreceptor (see [2,3] for recent reviews) has revealed it to be a G-protein-coupled, seven transmembrane domain, 41 kDa protein hnked to signaling pathways involving Ca 2 + and lnOSltol-phosphohpad metabolism and/or the inhibition of adenylate * Correspondence address Institute for Hormone and FertdJty Research, Umverslt) of Hamburg, Grandweg 64, D-22529 Hamburg, German~ Fax + 49 40 56190864 0167-0115;94/$7 00 © 1994 Elsevier Science B V All rights reserved SSDI 0 1 6 7 - 0 1 1 5 ( 9 4 ) 0 0 0 5 8 1
cyclase It was previously assumed that (see [2]), the AT2receptors belonged to the class of single transmembrane domain receptors In contrast, the cloning of the AT2receptors [4,5] established that they, too, belong to the seven transmembrane domain receptor family The signalling pathway associated with this type of receptor appears to involve an activation of tyroslne phosphatase and/or a reduction in the lntracellular cyclic G M P level, but an unambiguous identification of the signal transductlon pathway is yet to be achieved Now that the molecular biology of the two types of anglotensin receptors has been elucidated, it will not be long before exciting new developments follow, especially with respect to questions such as how anglotensln is able to activate so many different signalling pathways The detection by several laboratories of renlnanglotensln systems, including anglotensln receptors, in a wide variety of tissues has firmly estabhshed the existence of an extrarenal or tissue prorenln-renln-anglotensln system (PRAS) Recombinant DNA technology has played a major role in this The presence of an endogenous PRAS in tissues involved in cardiovascular homeostasis, hke reno-vascular tissue, is well documented [6] In
134
1A
,ltul, hopadh~a~ Reeuhttm~ Pepttde~ 53 11994~ I ~3-13s
addition, several other tissues and organs, including central neuroendocrlne tissues, brain and pituitary [7] ocular tissue [8], or steroldogenlc tissues like the adrenal, testes, ovaries and the fetoplacental umt [9] are now know to possess such intrinsic tissue prorenln-renln-anglotensln s~stems This has led to the concept that such local tissue P R A S perform regulatory functions within the tissue in an autocrlne' paracrlne manner Even an lntracrlne role [10] has been proposed, implying that anglotensm II could act at lntracellular sites within cells having a complete lntracellular renln-anglotensln s~stem Although, such concepts agree with experimental findlngs, their physiological relevance is not fully understood This varlet)' of wa~s anglotensln II ma) act plus the fact that its action can be mediated through a family of receptors linked to diverse slgnalhng pathways, offers a ver~ complicated but exciting research scenario Recent advances in several laboratories in developing both molecular biological as well as Immunological tools [11] (e g , highly specific antibodies to one or the other type of anglotensm receptors) suggest that we have reached a point where a major leap forward in our understanding of tissue P R A S is in the offing But despite the Intense actlVlt) m laboratories worldwide, there are still man~ unanswered questions For example, the involvement of ovarian P R A S in Inducing ovulation [12] and/or follicular atresla [ 1 3 - 1 5 ] appears to be reasonabl) certain, hut the basic mechanism herein remain to be elucidated Also questions such as whether P R A S is relevant for the regulation of male feruht3 ts ~et to bc addressed in depth It has become evident n o u that in extrarenal tissues expressing renln gene, it is prorenln and not renln x~hlch is preferentlall~ secreted out of cells [8,16,17] Therefore, there is a need to make direct assays available for specific determination of prorenln Such assa:ys for human prorenin, as ~ell as for prorenln from other species, should be able to b~pass the requirement of prior activation of Inactive prorenln to renln and should be free from errors
arising out of possible cr~oactlvatlon of prorenm in frozen samples Such assays will definitely help to Increase the pace of clinical as ~ell as experimental research in this area Because of the foregoing developments, it ~ as felt that the time ~ as ripe to organize a s5 mposlum to consider the advances made In recent )ears and to provide a forum for exchanging new ideas Although the pathophyslologlcal relevance of tissue P R A S has become lncreaslngl5 apparent during the past decade, as evident from the increasing number of scientific papers in this area, until no~ there has been no international symposium concerned solel? with the tissue P R A S Previous discussions on this topic have been hmlted to only one or t ~ o sessions as part of major congresses that included more general themes, such as hypertension and cardlo~ ascular blolog5 But now the subject of tissue P R A S has grown to such an extent that even all aspects of th~s theme cannot be an) more covered in a s)mposlum limited to t ~ o da~s only Therefore, it was decided to hmlt the Symposium to the discussion of the tissue P R A S only in respect to reproductive and endocrine organs Recognized experts m this area were invited as speakers and chairpersons for the ~arlous sessions A few abstracts from the submitted ones were selected )i~r short oral presentations In choosing the title and the theme of the S~mposlum, the a c m e and helpful exchange of Ideas ~lth Wdham G a n o n g (San Francisco CA) and M o h a n Ralzada (Galnesvllle, FL) ~ a s of llmnense help In a d d m o n to major organizational and financial assistance from the Institute for H o r m o n c and Fertlht3 Research Unlverslt) of Hamburg, the financial support from the G e r m a n Research Council ( D F G ) , Bonn, as welt as from a number of commercial organlzaUons, made this Symposium possible The complete proceedings of the S~mposlUln ~ dl be published b:y Plenuin Press, N e u York, NY, earl) in 1995
A K Mukhopadhla~ /Regulator~ Peptldes 53 (1994) 133-135
References [ 1] Tigerstedt, R and Bergmann, P G , Nlere und Krelslauf, Scand Arch Physlol, (1898) 223-271 [ 2] Bottarl, S P , De Gasparo, M Steckehngs, U M and Levens N R , Anglotensm II receptor subtypes CharacterlZatlon, slgnalhng mechanisms, and possible physiological lmphcatlons, Front Neuroendocrinol, 14 (1993) 123171 [ 3] Sandberg, K , Structural anal;rsls and regulation of anglotensm II receptors, Trends Endocnnol Metab, 5 (1994) 28-35 [ 4] Mukoyama, M , Nakajlma, M , Horluchl, M , Sasamura, H , Pratt, R E and Dzau, V J , Expression cloning of type-2 anglotensln II receptor re~eals a unique class of seventransmembrane receptors, J Blol Chem, 268 (1993) 24539-24542 [ 5] Kambayashl, Y Bardhan, S , Takahashl, K , Tsuzukl, S, Inul, H , Hamakubo T and Inagaml, T , Molecular cloning of a novel anglotensln II receptor lSOform involved in phosphot}roslnephosphatasemhlblt~on,J Biol Chem,268 (1993) 24543-24546 [ 6] MacFad~en, R J Role of the circulating and tissue-based remn-anglotensln system in the development of heart failure Imphcatlons for therapy, Cardiology, 83 (1993) 38-48 [ 7] Ganong, W F Blood, pituitary and brain renln-anglotensln s~rstems and regulation of secretion of anterior p~tultar~ gland, Front Neuroendocrmol, 14 (1993) 233-249 [ 8] Danser, A H J , Derk,~, F H M , Admlraal, P J J , Delnum, J De Jong, P T V M , and Schalekamp, M A D H , Anglotensm levels in the eye, Invest Opthalmol VJs Scl, 35 (1994) 1008-1018 [ 9] Phillips M I Speakman, E A and Klmura, B, Levels of
[ 10]
[ 11 ]
[ 12]
[13]
[14]
[ 15]
[16]
[17]
135
anglotensln and molecular biology of the tissue renInanglotensln systems, Regul Pept, 43 (1993) 1-20 De Mello, W C , Is an intracellular renln-anglotensln system involved in control of cell communication in heart 9, J Cardlovasc Pharm, 23 (1994) 640-646 Phillips, M I, Shen, L , Rlchards, E M and Ralzada, M K , Immunohistochemlcal mapping of angiotensln AT~ receptors in the brain, Regul Pept, 44 (1993) 95-107 Andrade-Gordon, P , Zrelk, T , Apa, R , and Naftolin, F , Role of anglotensln II in the process leading to ovulation, Blochem Pharmacol, 42 (1991) 715-719 Schultze, D , Brunswlg, B, Mukhopadhyay, A K , Renin and prorenln-llke actlwtles in bovine ovarian folhcles, Endocrlnolog}, 124 (1989) 1389-1398 Mukhopadhyay, A K , Holstein, K , Szkudhnski, M , Brunswlg-Splckenheier, B and Leidenberger, F A , The relationship between prorenm levels in follicular fluid and folhcular atresla in bovine ovaries, Endocrinology, 129 (1991) 2367-2375 Hsueh A J W and Bllhg, H , Control of folhcular atresta in the ovary, Curr Opinion Endocrlnol Diabetes, (1994) 192199 Yamaguchl T , Nalto, Z , Stoner, G D , Franco-Saenz, R and Mu|row, P J , Role of the adrenal renln-angiotensln system on adrenocortlcotrophlc hormone- and potassium° stimulated aldosterone production by rat adrenal glomerulosa cells in monolayer culture, Hypertension, 16 (1990) 635-641 Brunswlg-Splckenheler, B and Mukhopadh)ay, A K , Inhibitory effects of a tumor-promoting phorbol ester on lutelmzlng hormone-stimulated reran and prorenln production b~ cultured bovine theca cells, Endocrinology, (1990) 2157-2165
Regulatory Pept~des 53 (1994) 133-135
Introductory comments
Tissue prorenin-renin-angiotensin systems: local regulatory roles in reproductive and endocrine organs Areal K Mukhopadhyay* Hamburg Germam, Jufi 15-16 1994 A Satelhte S~mpo~tum to the IH European Endocrinology, Congress Amsterdam The Netherland~
In 1898, nearly a century ago, renln was discovered by Tlgerstedt and Bergman [ 1] During the most of the subsequent period, the renln-anglotensln system has been considered to be primarily a mixed enzymehormonal mechanism for the regulation of cardiovascular homeostasis But, during the last decade, important advances in two areas have revealed new facets in renan-anglotensln research One was the synthesis of a number of non-peptlde anglotensln II receptor antagonists and the other was an understanding of the molecular biology of the renlnanglotensln system The avallablhty of non-peptlde receptor antagonists and of molecular biology tools have made it possible now to determine the molecular pharmacology of a number of types and subtypes of anglotensln receptors [2,3] The cloning of the mammahan ATlreceptor (see [2,3] for recent reviews) has revealed it to be a G-protein-coupled, seven transmembrane domain, 41 kDa protein hnked to signaling pathways involving Ca 2 + and lnOSltol-phosphohpad metabolism and/or the inhibition of adenylate * Correspondence address Institute for Hormone and FertdJty Research, Umverslt) of Hamburg, Grandweg 64, D-22529 Hamburg, German~ Fax + 49 40 56190864 0167-0115;94/$7 00 © 1994 Elsevier Science B V All rights reserved SSDI 0 1 6 7 - 0 1 1 5 ( 9 4 ) 0 0 0 5 8 1
cyclase It was previously assumed that (see [2]), the AT2receptors belonged to the class of single transmembrane domain receptors In contrast, the cloning of the AT2receptors [4,5] established that they, too, belong to the seven transmembrane domain receptor family The signalling pathway associated with this type of receptor appears to involve an activation of tyroslne phosphatase and/or a reduction in the lntracellular cyclic G M P level, but an unambiguous identification of the signal transductlon pathway is yet to be achieved Now that the molecular biology of the two types of anglotensin receptors has been elucidated, it will not be long before exciting new developments follow, especially with respect to questions such as how anglotensln is able to activate so many different signalling pathways The detection by several laboratories of renlnanglotensln systems, including anglotensln receptors, in a wide variety of tissues has firmly estabhshed the existence of an extrarenal or tissue prorenln-renln-anglotensln system (PRAS) Recombinant DNA technology has played a major role in this The presence of an endogenous PRAS in tissues involved in cardiovascular homeostasis, hke reno-vascular tissue, is well documented [6] In
134
1A
,ltul, hopadh~a~ Reeuhttm~ Pepttde~ 53 11994~ I ~3-13s
addition, several other tissues and organs, including central neuroendocrlne tissues, brain and pituitary [7] ocular tissue [8], or steroldogenlc tissues like the adrenal, testes, ovaries and the fetoplacental umt [9] are now know to possess such intrinsic tissue prorenln-renln-anglotensln s~stems This has led to the concept that such local tissue P R A S perform regulatory functions within the tissue in an autocrlne' paracrlne manner Even an lntracrlne role [10] has been proposed, implying that anglotensm II could act at lntracellular sites within cells having a complete lntracellular renln-anglotensln s~stem Although, such concepts agree with experimental findlngs, their physiological relevance is not fully understood This varlet)' of wa~s anglotensln II ma) act plus the fact that its action can be mediated through a family of receptors linked to diverse slgnalhng pathways, offers a ver~ complicated but exciting research scenario Recent advances in several laboratories in developing both molecular biological as well as Immunological tools [11] (e g , highly specific antibodies to one or the other type of anglotensm receptors) suggest that we have reached a point where a major leap forward in our understanding of tissue P R A S is in the offing But despite the Intense actlVlt) m laboratories worldwide, there are still man~ unanswered questions For example, the involvement of ovarian P R A S in Inducing ovulation [12] and/or follicular atresla [ 1 3 - 1 5 ] appears to be reasonabl) certain, hut the basic mechanism herein remain to be elucidated Also questions such as whether P R A S is relevant for the regulation of male feruht3 ts ~et to bc addressed in depth It has become evident n o u that in extrarenal tissues expressing renln gene, it is prorenln and not renln x~hlch is preferentlall~ secreted out of cells [8,16,17] Therefore, there is a need to make direct assays available for specific determination of prorenln Such assa:ys for human prorenin, as ~ell as for prorenln from other species, should be able to b~pass the requirement of prior activation of Inactive prorenln to renln and should be free from errors
arising out of possible cr~oactlvatlon of prorenm in frozen samples Such assays will definitely help to Increase the pace of clinical as ~ell as experimental research in this area Because of the foregoing developments, it ~ as felt that the time ~ as ripe to organize a s5 mposlum to consider the advances made In recent )ears and to provide a forum for exchanging new ideas Although the pathophyslologlcal relevance of tissue P R A S has become lncreaslngl5 apparent during the past decade, as evident from the increasing number of scientific papers in this area, until no~ there has been no international symposium concerned solel? with the tissue P R A S Previous discussions on this topic have been hmlted to only one or t ~ o sessions as part of major congresses that included more general themes, such as hypertension and cardlo~ ascular blolog5 But now the subject of tissue P R A S has grown to such an extent that even all aspects of th~s theme cannot be an) more covered in a s)mposlum limited to t ~ o da~s only Therefore, it was decided to hmlt the Symposium to the discussion of the tissue P R A S only in respect to reproductive and endocrine organs Recognized experts m this area were invited as speakers and chairpersons for the ~arlous sessions A few abstracts from the submitted ones were selected )i~r short oral presentations In choosing the title and the theme of the S~mposlum, the a c m e and helpful exchange of Ideas ~lth Wdham G a n o n g (San Francisco CA) and M o h a n Ralzada (Galnesvllle, FL) ~ a s of llmnense help In a d d m o n to major organizational and financial assistance from the Institute for H o r m o n c and Fertlht3 Research Unlverslt) of Hamburg, the financial support from the G e r m a n Research Council ( D F G ) , Bonn, as welt as from a number of commercial organlzaUons, made this Symposium possible The complete proceedings of the S~mposlUln ~ dl be published b:y Plenuin Press, N e u York, NY, earl) in 1995
A K Mukhopadhla~ /Regulator~ Peptldes 53 (1994) 133-135
References [ 1] Tigerstedt, R and Bergmann, P G , Nlere und Krelslauf, Scand Arch Physlol, (1898) 223-271 [ 2] Bottarl, S P , De Gasparo, M Steckehngs, U M and Levens N R , Anglotensm II receptor subtypes CharacterlZatlon, slgnalhng mechanisms, and possible physiological lmphcatlons, Front Neuroendocrinol, 14 (1993) 123171 [ 3] Sandberg, K , Structural anal;rsls and regulation of anglotensm II receptors, Trends Endocnnol Metab, 5 (1994) 28-35 [ 4] Mukoyama, M , Nakajlma, M , Horluchl, M , Sasamura, H , Pratt, R E and Dzau, V J , Expression cloning of type-2 anglotensln II receptor re~eals a unique class of seventransmembrane receptors, J Blol Chem, 268 (1993) 24539-24542 [ 5] Kambayashl, Y Bardhan, S , Takahashl, K , Tsuzukl, S, Inul, H , Hamakubo T and Inagaml, T , Molecular cloning of a novel anglotensln II receptor lSOform involved in phosphot}roslnephosphatasemhlblt~on,J Biol Chem,268 (1993) 24543-24546 [ 6] MacFad~en, R J Role of the circulating and tissue-based remn-anglotensln system in the development of heart failure Imphcatlons for therapy, Cardiology, 83 (1993) 38-48 [ 7] Ganong, W F Blood, pituitary and brain renln-anglotensln s~rstems and regulation of secretion of anterior p~tultar~ gland, Front Neuroendocrmol, 14 (1993) 233-249 [ 8] Danser, A H J , Derk,~, F H M , Admlraal, P J J , Delnum, J De Jong, P T V M , and Schalekamp, M A D H , Anglotensm levels in the eye, Invest Opthalmol VJs Scl, 35 (1994) 1008-1018 [ 9] Phillips M I Speakman, E A and Klmura, B, Levels of
[ 10]
[ 11 ]
[ 12]
[13]
[14]
[ 15]
[16]
[17]
135
anglotensln and molecular biology of the tissue renInanglotensln systems, Regul Pept, 43 (1993) 1-20 De Mello, W C , Is an intracellular renln-anglotensln system involved in control of cell communication in heart 9, J Cardlovasc Pharm, 23 (1994) 640-646 Phillips, M I, Shen, L , Rlchards, E M and Ralzada, M K , Immunohistochemlcal mapping of angiotensln AT~ receptors in the brain, Regul Pept, 44 (1993) 95-107 Andrade-Gordon, P , Zrelk, T , Apa, R , and Naftolin, F , Role of anglotensln II in the process leading to ovulation, Blochem Pharmacol, 42 (1991) 715-719 Schultze, D , Brunswlg, B, Mukhopadhyay, A K , Renin and prorenln-llke actlwtles in bovine ovarian folhcles, Endocrlnolog}, 124 (1989) 1389-1398 Mukhopadhyay, A K , Holstein, K , Szkudhnski, M , Brunswlg-Splckenheier, B and Leidenberger, F A , The relationship between prorenm levels in follicular fluid and folhcular atresla in bovine ovaries, Endocrinology, 129 (1991) 2367-2375 Hsueh A J W and Bllhg, H , Control of folhcular atresta in the ovary, Curr Opinion Endocrlnol Diabetes, (1994) 192199 Yamaguchl T , Nalto, Z , Stoner, G D , Franco-Saenz, R and Mu|row, P J , Role of the adrenal renln-angiotensln system on adrenocortlcotrophlc hormone- and potassium° stimulated aldosterone production by rat adrenal glomerulosa cells in monolayer culture, Hypertension, 16 (1990) 635-641 Brunswlg-Splckenheler, B and Mukhopadh)ay, A K , Inhibitory effects of a tumor-promoting phorbol ester on lutelmzlng hormone-stimulated reran and prorenln production b~ cultured bovine theca cells, Endocrinology, (1990) 2157-2165