Abstract
There is compelling physiological evidence of binding and uptake of renin and prorenin in tissues. A number of molecules with the ability to bind renin and prorenin have been identified and have been characterized to varying degrees. It remains unclear, however, just how many renin/prorenin binding proteins and receptors exist and what their physiological functions may be. The possible functions of renin/prorenin binding and uptake are manifold, and include clearance of renin and prorenin from the circulation, local generation of angiotensins, activation of prorenin on the cell surface, trafficking of prorenin between cellular and extracellular compartments as part of a complex processing machinery, and signal transduction both via direct receptor mediated signaling, and via modulation of O-linkage of N-acetyl-glucosamine to cellular proteins. Some of these functions may involve single renin/prorenin binding sites or receptors, while others may require multiple binding sites and receptors. This review describes the physiological studies that have provided evidence of renin/prorenin uptake from the circulation, summarizes our knowledge of renin/prorenin binding proteins and receptors, and postulates new roles for renin/prorenin binding and uptake in tissues.
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von Lutterotti N, Catanzaro DF, Sealey JE, Laragh JH : Renin is not synthesized by cardiac and extrarenal vascular tissues: a review of experimental evidence. Circulation 1994; 89: 458–470.
Saris JJ, Derkx FH, De Bruin RJ, et al: High-affinity prorenin binding to cardiac man-6-P/IGF-II receptors precedes proteolytic activation to renin. Am J Physiol Heart Circ Physiol 2001; 280: H1706–H1715.
Sealey JE, von Lutterotti N, Rubattu S, et al: The greater renin system. Its prorenin-directed vasodilator limb. Relevance to diabetes mellitus, pregnancy, and hypertension. Am J Hypertens 1991; 4: 972–977.
Hsueh WA, Baxter JD : Human prorenin. Hypertension 1991; 17: 469–477.
Kawamura M, Ikemoto F, Funakawa S, Yamamoto K : Characteristics of a renin-binding substance for the conversion of renin into a higher-molecular-weight form in the dog. Clin Sci 1979; 57: 345–350.
Campbell DJ, Valentijn AJ : Identification of vascular renin-binding proteins by chemical cross-linking: inhibition of binding of renin by renin inhibitors. J Hypertens 1994; 12: 879–890.
Sealey JE, Catanzaro DF, Lavin TN, et al: Specific prorenin/renin binding (ProBP). Identification and characterization of a novel membrane site. Am J Hypertens 1996; 9: 491–502.
Admiraal PJ, van Kesteren CA, Danser AHJ, Derkx FH, Sluiter W, Schalekamp MADH : Uptake and proteolytic activation of prorenin by cultured human endothelial cells. J Hypertens 1999; 17: 621–629.
Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer JD : Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 2002; 109: 1417–1427.
Berk BC : Angiotensin II signal transduction in vascular smooth muscle: pathways activated by specific tyrosine kinases. J Am Soc Nephrol 1999; 10: S62–S68.
Naftilan AJ, Pratt RE, Dzau VJ : Induction of platelet-derived growth factor A-chain and c-myc gene expressions by angiotensin II in cultured rat vascular smooth muscle cells. J Clin Invest 1989; 83: 1419–1424.
Geisterfer AA, Peach MJ, Owens GK : Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cells. Circ Res 1988; 62: 749–756.
Sung CP, Arleth AJ, Storer BL, Ohlstein EH : Angiotensin type 1 receptors mediate smooth muscle proliferation and endothelin biosynthesis in rat vascular smooth muscle. J Pharmacol Exp Ther 1994; 271: 429–437.
Su EJ, Lombardi DM, Siegal J, Schwartz SM : Angiotensin II induces vascular smooth muscle cell replication independent of blood pressure. Hypertension 1998; 31: 1331–1337.
Daemen MJ, Lombardi DM, Bosman FT, Schwartz SM : Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall. Circ Res 1991; 68: 450–456.
Harrison DG : Endothelial function and oxidant stress. Clin Cardiol 1997; 20: 11–17.
Taniyama Y, Griendling KK : Reactive oxygen species in the vasculature: molecular and cellular mechanisms. Hypertension 2003; 42: 1075–1081.
Tigerstedt R, Bergman PG : Niere und Kreislauf. Skand Arch Physiol 1898; 8: 223–271.
Bing J : Mechanism of the increased sensitivity to renin in nephrectomized animals. Acta Pathol Scand 1963; 60: 311.
Blaquier P, Hoobler SW, Schroeder J, Gomez A, Kreulen T : Effect of bilateral nephrectomy on pressor response to renin. Am J Physiol 1962; 203: 339–342.
Carretero O, Gross F : Evidence for humoral factors participating in the renin-substrate reaction. Circ Res 1966; 20•21 ( Suppl II): 115–127.
Swales JD, Thurston H : Generation of angiotensin II at peripheral vascular level: studies using angiotensin II antisera. Clin Sci Mol Med 1973; 45: 691–700.
Thurston H, Swales JD : Action of angiotensin antagonists and antiserum upon the pressor response to renin: further evidence for the local generation of angiotensin II. Clin Sci Mol Med 1974; 46: 273–276.
Thurston H, Swales JD : Blood pressure response of nephrectomized hypertensive rats to converting enzyme inhibition: evidence for persistent vascular renin activity. Clin Sci Mol Med 1977; 52: 299–304.
Thurston H, Hurst BC, Bing RF, Swales JD : Role of persistent vascular renin after bilateral nephrectomy in Goldblatt-two kidney hypertension. Clin Sci Mol Med Suppl 1978; 4: 23s–26s.
Thurston H, Swales JD, Bing RF, Hurst BC, Marks ES : Vascular renin-like activity and blood pressure maintenance in the rat. Studies of the effect of changes in sodium balance, hypertension and nephrectomy. Hypertension 1979; 1: 643–649.
Swales JD : Arterial wall or plasma renin in hypertension. Clin Sci 1979; 56: 293–298.
Loudon M, Bing RF, Swales JD, Thurston H : Vascular renin as a determinant of the circulatory response to renin. Clin Exp Hypertens 1982; 4: 2049–2061.
Loudon M, Bing RF, Thurston H, Swales JD : Arterial wall uptake of renal renin and blood pressure control. Hypertension 1983; 5: 629–634.
Swales JD, Loudon M, Bing RF, Thurston H : Renin in the arterial wall. Clin Exp Hypertens 1983; 5: 1127–1136.
Bing J, Nielsen K : Role of the renin-system in normo- and hypertension. Effect of angiotensin-inhibitor (1-sar-8-ala-angiotensin II) on the blood pressure of conscious or anaesthetized normal, nephrectomized and renal hypertensive rats. Acta Pathol Microbiol Scand 1973; 81: 254–262.
Campbell DJ, Lawrence AC, Towrie A, Kladis A, Valentijn AJ : Differential regulation of angiotensin peptide levels in plasma and kidney of the rat. Hypertension 1991; 18: 763–773.
Admiraal PJJ, Danser AHJ, de Jong M, Pieterman H, Derkx FHM, Schalekamp MADH : Regional angiotensin II production in essential hypertension and renal artery stenosis. Hypertension 1993; 21: 173–184.
Seikaly MG, Arant BSJ, Seney FD Jr : Endogenous angiotensin concentrations in specific intrarenal fluid compartments of the rat. J Clin Invest 1990; 86: 1352–1357.
Braam B, Mitchell KD, Fox J, Navar LG : Proximal tubular secretion of of angiotensin II in rats. Am J Physiol 1993; 264: F891–F898.
Veniant M, Menard J, Bruneval P, Morley S, Gonzales MF, Mullins J : Vascular damage without hypertension in transgenic rats expressing prorenin exclusively in the liver. J Clin Invest 1996; 98: 1966–1970.
Prescott G, Silversides DW, Chiu SM, Reudelhuber TL : Contribution of circulating renin to local synthesis of angiotensin peptides in the heart. Physiol Genomics 2000; 4: 67–73.
Prescott G, Silversides DW, Reudelhuber TL : Tissue activity of circulating prorenin. Am J Hypertens 2002; 15: 280–285.
Mazzolai L, Pedrazzini T, Nicoud F, Gabbiani G, Brunner HR, Nussberger J : Increased cardiac angiotensin II levels induce right and left ventricular hypertrophy in normotensive mice. Hypertension 2000; 35: 985–991.
Dengler H : Concerning a renin-like active substance in extracts from arteries. Naunyn Schmiedebergs Arch Pharmacol 1956; 227: 481–487.
Gould AB, Skeggs LT, Kahn JR : The presence of renin activity in blood vessel walls. J Exp Med 1964; 119: 389–399.
Swales JD, Abramovici A, Beck F, Bing RF, Loudon M, Thurston H : Arterial wall renin. J Hypertens Suppl 1983; 1: 17–22.
Skeggs LT, Dorer FE, Lentz KE, Kahn JR, Emancipator S : A new mechanism in one-kidney, one-clip hypertension. Hypertension 1985; 7: 72–80.
Thurston H, Swales JD : Comparison of angiotensin II antagonist and antiserum infusion with nephrectomy in the rat with two-kidney goldblatt hypertension. Circ Res 1974; 35: 325–329.
Danser AHJ, van Kats JP, Admiraal PJ, et al: Cardiac renin and angiotensins. Uptake from plasma versus in situ synthesis. Hypertension 1994; 24: 37–48.
Heller LJ, Opsahl JA, Wernsing SE, Saxena R, Katz SA : Myocardial and plasma renin-angiotensinogen dynamics during pressure-induced cardiac hypertrophy. Am J Physiol 1998; 274: R849–R856.
Lindpaintner K, Jin MW, Niedermaier N, Wilhelm MJ, Ganten D : Cardiac angiotensinogen and its local activation in the isolated perfused beating heart. Circ Res 1990; 67: 564–573.
de Lannoy LM, Danser AHJ, Bouhuizen AM, Saxena PR, Schalekamp MADH : Localization and production of angiotensin II in the isolated perfused rat heart. Hypertension 1998; 31: 1111–1117.
Rosivall L, Razga Z, Mirzahosseini S, Tornoci L : Endothelial permeability of the afferent arteriole and its changes as the result of alteration in the activity of the renin-angiotensin system. J Am Soc Nephrol 1999; 10 ( Suppl 11): S172–S177.
Rosivall L, Taugner R : The morphological basis of fluid balance in the interstitium of the juxtaglomerular apparatus. Cell Tissue Res 1986; 243: 525–533.
Tiedemann K, Egerer G : Vascularization and glomerular ultrastructure in the pig mesonephros. Cell Tissue Res 1984; 238: 165–175.
Bendayan M : Morphological and cytochemical aspects of capillary permeability. Microsc Res Tech 2002; 57: 327–349.
Edens H, Parkos C : Modulation of epithelial and endothelial paracellular permeability by leukocytes. Adv Drug Deliv Rev 2000; 41: 315–328.
de Lannoy LM, Danser AHJ, van Kats JP, Schoemaker RG, Saxena PR, Schalekamp MADH : Renin-angiotensin system components in the interstitial fluid of the isolated perfused rat heart. Local production of angiotensin I. Hypertension 1997; 29: 1240–1251.
Takaori K, Funakawa S, Ikemoto F, Yamamoto K : Low molecular weight renin as a storage form in renin granules of the dog. Biochem Biophys Res Commun 1979; 91: 214–221.
Funakawa S, Ikemoto F, Kawamura M, Yamamoto K : Relationship between molecular weight conversion and renin activity in dog renal renin. Jpn Circ J 1979; 43: 183–189.
Funakawa S, Funae Y, Yamamoto K : Conversion between renin and high-molecular-weight renin in the dog. Biochem J 1979; 176: 977–981.
Ikemoto F, Takaori K, Iwao H, Yamamoto K : Intrarenal localization of renin binding substance in rats. Life Sci 1982; 31: 1011–1016.
Takaori K, Iwao H, Ikemoto F, Yamamoto K : Specific distribution of renin binding protein in rat and dog kidney. Clin Exp Hypertens 1982; 4: 2097–2105.
Murakami K, Hirose S, Chino S, Ueno N, Miyazaki H : Properties of renin-binding protein. Clin Exp Hypertens 1982; 4: 2073–2081.
Schmitz C, Gotthardt M, Hinderlich S, et al: Normal blood pressure and plasma renin activity in mice lacking the renin-binding protein, a cellular renin inhibitor. J Biol Chem 2000; 275: 15357–15362.
Leckie BJ, Lacy PS, Lidder S : The expression of renin-binding protein and renin in the kidneys of rats with two-kidney one-clip hypertension. J Hypertens 2000; 18: 935–943.
Inoue H, Takahashi S, Miyake Y : Modulation of active renin secretion by renin-binding protein (RnBP) in mouse pituitary AtT-20 cells transfected with human renin and RnBP cDNAs. J Biochem (Tokyo) 1992; 111: 407–412.
Maru I, Ohta Y, Murata K, Tsukada Y : Molecular cloning and identification of N-acyl-D-glucosamine 2-epimerase from porcine kidney as a renin-binding protein. J Biol Chem 1996; 271: 16294–16299.
Weiss P, Tietze F, Gahl WA, Seppala R, Ashwell G : Identification of the metabolic defect in sialuria. J Biol Chem 1989; 264: 17635–17636.
Bohlmeyer T, Ferdensi A, Bristow MR, Takahashi S, Zisman LS : Selective activation of N-acyl-D-glucosamine 2-epimerase expression in failing human heart ventricular myocytes. J Card Fail 2003; 9: 59–68.
Boehmelt G, Wakeham A, Elia A, et al: Decreased UDP-GlcNAc levels abrogate proliferation control in EMeg32-deficient cells. EMBO J 2000; 19: 5092–5104.
Wells L, Vosseller K, Hart GW : Glycosylation of nucleocytoplasmic proteins: signal transduction and O-GlcNAc. Science 2001; 291: 2376–2378.
Takahashi S, Kumagai M, Shindo S, Saito K, Kawamura Y : Renin inhibits N-acetyl-D-glucosamine 2-epimerase (renin-binding protein). J Biochem (Tokyo) 2000; 128: 951–956.
Clausmeyer S, Reinecke A, Farrenkopf R, Unger T, Peters J : Tissue-specific expression of a rat renin transcript lacking the coding sequence for the prefragment and its stimulation by myocardial infarction. Endocrinology 2000; 141: 2963–2970.
Clausmeyer S, Sturzebecher R, Peters J : An alternative transcript of the rat renin gene can result in a truncated prorenin that is transported into adrenal mitochondria. Circ Res 1999; 84: 337–344.
Peters J, Clausmeyer S : Intracellular sorting of renin: cell type specific differences and their consequences. J Mol Cell Cardiol 2002; 34: 1561–1568.
Funakawa S, Funae Y, Yamamoto K : Conversion between renin and high-molecular-weight renin in the dog. Biochem J 1978; 176: 977–981.
Funakawa S, Higashio T, Yamamoto K : Renin release from renin granules in the dog. Clin Sci Mol Med 1978; 55: 11–14.
Dennis PA, Rifkin DB : Cellular activation of latent transforming growth factor beta requires binding to the cation-independent mannose 6-phosphate/insulin-like growth factor type II receptor. Proc Natl Acad Sci U S A 1991; 88: 580–584.
van den Eijnden MM, Saris JJ, de Bruin RJ, et al: Prorenin accumulation and activation in human endothelial cells: importance of mannose 6-phosphate receptors. Arterioscler Thromb Vasc Biol 2001; 21: 911–916.
Saris JJ, Derkx FH, Lamers JMJ, Saxena PR, Schalekamp MA, Danser AHJ : Cardiomyocytes bind and activate native human prorenin: role of soluble mannose 6-phosphate receptors. Hypertension 2001; 37: 710–715.
Cook JL, Zhang Z, Re RN : In vitro evidence for an intracellular site of angiotensin action. Circ Res 2001; 89: 1138–1146.
Danser AHJ : Local renin-angiotensin systems: the unanswered questions. Int J Biochem Cell Biol 2003; 35: 759–768.
Schuijt MP, Danser AHJ : Cardiac angiotensin ii: an intracrine hormone? Am J Hypertens 2002; 15: 1109–1116.
Saris JJ, van den Eijnden MM, Lamers JMJ, Saxena PR, Schalekamp MADH, Danser AHJ : Prorenin-induced myocyte proliferation: no role for intracellular angiotensin II. Hypertension 2002; 39: 573–577.
Mullins JJ, Peters J, Ganten D : Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature 1990; 344: 541–544.
Bachmann S, Peters J, Engler E, Ganten D, Mullins J : Transgenic rats carrying the mouse renin gene—morphological characterization of a low-renin hypertension model. Kidney Int 1992; 41: 24–36.
Bohm M, Lee MA, Kreutz R, et al: Angiotensin II receptor blockade in TGR(mREN2)27: effects of renin-angiotensin-system gene expression and cardiovascular functions. J Hypertens 1995; 13: 891–899.
Peters J, Farrenkopf R, Clausmeyer S, et al: Functional significance of prorenin internalization in the rat heart. Circ Res 2002; 90: 1135–1141.
Kantachuvesiri S, Fleming S, Peters J, et al: Controlled hypertension, a transgenic toggle switch reveals differential mechanisms underlying vascular disease. J Biol Chem 2001; 276: 36727–36733.
Yan Y, Chen R, Pitarresi T, et al: Kidney is the only source of human plasma renin in 45 kb hREN transgenic mice. Circ Res 1998; 83: 1279–1288.
Yan Y, Hu L, Chen R, Laragh JH, Sealey JE, Catanzaro DF : Appropriate regulation of human renin gene expression and secretion in 45 kb human renin transgenic mice. Hypertension 1998; 32: 205–214.
Nguyen G, Burckle C, Sraer JD : The renin receptor: the facts, the promise and the hope. Curr Opin Nephrol Hypertens 2003; 12: 51–55.
Nguyen G, Burckle CA, Sraer JD : Renin/prorenin-receptor biochemistry and functional significance. Curr Hypertens Rep 2004; 6: 129–132.
Herzog V, Neumuller W, Holzmann B : Thyroglobulin, the major and obligatory exportable protein of thyroid follicle cells, carries the lysosomal recognition marker mannose-6-phosphate. EMBO J 1987; 6: 555–560.
van den Eijnden MM, de Bruin RJ, de Wit E, et al: Transendothelial transport of renin-angiotensin system components. J Hypertens 2002; 20: 2029–2037.
Ichihara A, Hayashi M, Hirota N, et al: Angiotensin II type 2 receptor inhibits prorenin processing in juxtaglomerular cells. Hypertens Res 2003; 26: 915–921.
Hirota N, Ichihara A, Koura Y, Tada Y, Hayashi M, Saruta T : Transmural pressure control of prorenin processing and secretion in diabetic rat juxtaglomerular cells. Hypertens Res 2003; 26: 493–501.
McClain DA, Crook ED : Hexosamines and insulin resistance. Diabetes 1996; 45: 1003–1009.
Hart GW : Dynamic O-linked glycosylation of nuclear and cytoskeletal proteins. Annu Rev Biochem 1997; 66: 315–335.
Gilbert RE, Krum H, Wilkinson-Berka J, Kelly DJ : The renin-angiotensin system and the long-term complications of diabetes: pathophysiological and therapeutic considerations. Diabet Med 2003; 20: 607–621.
Hsueh WA : Treatment of type 2 diabetic nephropathy by blockade of the renin-angiotensin system: a comparison of angiotensin-converting-enzyme inhibitors and angiotensin receptor antagonists. Curr Opin Pharmacol 2002; 2: 182–188.
Umeda M, Kanda T, Murakami M : Effects of angiotensin II receptor antagonists on insulin resistance syndrome and leptin in sucrose-fed spontaneously hypertensive rats. Hypertens Res 2003; 26: 485–492.
Packer M, Coats AJ, Fowler MB, et al: Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344: 1651–1658.
Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Hersberger R : Effects of carvedilol on left ventricular dysfunction and mortality in diabetic versus non-diabetic patients with ischemic or non-ischemic dilated cardiomyopathy. Circulation 1996; 94: I664A.
Blumenfeld JD, Sealey JE, Mann SJ, et al: Beta-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensin-aldosterone system in normotensive and hypertensive subjects. Am J Hypertens 1999; 12: 451–459.
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Catanzaro, D. Physiological Relevance of Renin/Prorenin Binding and Uptake. Hypertens Res 28, 97–105 (2005). https://doi.org/10.1291/hypres.28.97
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DOI: https://doi.org/10.1291/hypres.28.97
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