Abstract
The intrarenal renin–angiotensin system is critical for the regulation of tubule sodium reabsorption, renal haemodynamics and blood pressure. The excretion of renin in urine can result from its increased filtration, the inhibition of renin reabsorption by megalin in the proximal tubule, or its secretion by the principal cells of the collecting duct. Modest increases in circulating or intrarenal angiotensin II (ANGII) stimulate the synthesis and secretion of angiotensinogen in the proximal tubule, which provides sufficient substrate for collecting duct-derived renin to form angiotensin I (ANGI). In models of ANGII-dependent hypertension, ANGII suppresses plasma renin, suggesting that urinary renin is not likely to be the result of increased filtered load. In the collecting duct, ANGII stimulates the synthesis and secretion of prorenin and renin through the activation of ANGII type 1 receptor (AT1R) expressed primarily by principal cells. The stimulation of collecting duct-derived renin is enhanced by paracrine factors including vasopressin, prostaglandin E2 and bradykinin. Furthermore, binding of prorenin and renin to the prorenin receptor in the collecting duct evokes a number of responses, including the non-proteolytic enzymatic activation of prorenin to produce ANGI from proximal tubule-derived angiotensinogen, which is then converted into ANGII by luminal angiotensin-converting enzyme; stimulation of the epithelial sodium channel (ENaC) in principal cells; and activation of intracellular pathways linked to the upregulation of cyclooxygenase 2 and profibrotic genes. These findings suggest that dysregulation of the renin–angiotensin system in the collecting duct contributes to the development of hypertension by enhancing sodium reabsorption and the progression of kidney injury.
Key points
-
Renin-expressing cells are present in various components of the nephron, including the juxtaglomerular apparatus, glomeruli, proximal tubules, connecting tubules and collecting ducts.
-
Collecting duct-derived renin is stimulated by a number of factors, including angiotensin II, prostaglandin E2, bradykinin and vasopressin, which contribute to the paracrine control of sodium reabsorption in the distal nephron.
-
Binding of prorenin and renin to the prorenin receptor, expressed by collecting duct cells, enhances the formation of intratubular angiotensin II and promotes kidney fibrosis.
-
In models of angiotensin II-dependent hypertension, components of the renin–angiotensin system, including proximal tubule-derived angiotensinogen, collecting duct-derived renin and the prorenin receptor expressed in the collecting duct, together facilitate the sustained formation of intratubular angiotensin II and stimulation of profibrotic factors leading to kidney tubule damage.
-
Circulating renin that is filtered and not reabsorbed by megalin in the proximal tubule may also contribute to renin in the urine.
-
The renin–angiotensin system in the distal nephron is complex and not fully understood but seems to involve coordinated actions to regulate intrarenal and intratubular angiotensin II, sodium reabsorption, blood pressure and fluid–electrolyte homeostasis.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ferrario, C. M. & Schiavone, M. T. The renin angiotensin system: importance in physiology and pathology. Cleve. Clin. J. Med. 56, 439–446 (1989).
Sparks, M. A., Crowley, S. D., Gurley, S. B., Mirotsou, M. & Coffman, T. M. Classical renin-angiotensin system in kidney physiology. Compr. Physiol. 4, 1201–1228 (2014).
Stokes, G. S. The renin angiotensin system — its physiology and role in disease states. Anaesth. Intensive Care 11, 369–376 (1983).
Sequeira-Lopez, M. L. S. et al. The earliest metanephric arteriolar progenitors and their role in kidney vascular development. Am. J. Physiol. Reg. 308, R138–R149 (2015).
Brunskill, E. W. et al. Genes that confer the identity of the renin cell. J. Am. Soc. Nephrol. 22, 2213–2225 (2011).
Rohrwasser, A. et al. Elements of a paracrine tubular renin-angiotensin system along the entire nephron. Hypertension 34, 1265–1274 (1999).
Prieto-Carrasquero, M. C. et al. AT(1) receptor- mediated enhancement of collecting duct renin in angiotensin II-dependent hypertensive rats. Am. J. Physiol. Renal Physiol. 289, F632–F637 (2005).
Gonzalez, A. A., Salinas-Parra, N., Leach, D., Navar, L. G. & Prieto, M. C. PGE2 upregulates renin through E-prostanoid receptor 1 via PKC/cAMP/CREB pathway in M-1 cells. Am. J. Physiol. Renal Physiol. 313, F1038–F1049 (2017).
Gonzalez, A. A. et al. Angiotensin II stimulates renin in inner medullary collecting duct cells via protein kinase C and independent of epithelial sodium channel and mineralocorticoid receptor activity. Hypertension 57, 594–599 (2011).
Gonzalez, A. A. et al. Vasopressin/V2 receptor stimulates renin synthesis in the collecting duct. Am. J. Physiol. Renal Physiol. 310, F284–F293 (2016).
Lara, L. S., Bourgeois, C. R. T., El-Dahr, S. S. & Prieto, M. C. Bradykinin/B-2 receptor activation regulates renin in M-1 cells via protein kinase C and nitric oxide. Physiol. Rep. 5, e13211 (2017).
Prieto-Carrasquero, M. C. et al. Collecting duct renin is upregulated in both kidneys of 2-kidney, 1-clip Goldblatt hypertensive rats. Hypertension 51, 1590–1596 (2008).
Tang, J. et al. Urinary renin in patients and mice with diabetic kidney disease. Hypertension 74, 83–94 (2019).
Saito, T., Urushihara, M., Kotani, Y., Kagami, S. & Kobori, H. Increased urinary angiotensinogen is precedent to increased urinary albumin in patients with type 1 diabetes. Am. J. Med. Sci. 338, 478–480 (2009).
van den Heuvel, M. et al. Urinary renin, but not angiotensinogen or aldosterone, reflects the renal renin-angiotensin-aldosterone system activity and the efficacy of renin-angiotensin-aldosterone system blockade in the kidney. J. Hypertens. 29, 2147–2155 (2011).
Kang, J. J. et al. The collecting duct is the major source of prorenin in diabetes. Hypertension 51, 1597–1604 (2008).
Gonzalez, A. A., Lara, L. S., Luffman, C., Seth, D. M. & Prieto, M. C. Soluble form of the (Pro) renin receptor is augmented in the collecting duct and urine of chronic angiotensin II-dependent hypertensive rats. Hypertension 57, 859–864 (2011).
Gonzalez, A. A. et al. (Pro)renin receptor activation increases profibrotic markers and fibroblast-like phenotype through MAPK-dependent ROS formation in mouse renal collecting duct cells. Clin. Exp. Pharmacol. Physiol. 44, 1134–1144 (2017).
Castrop, H. et al. Physiology of kidney renin. Physiol. Rev. 90, 607–673 (2010).
Muller, M. W. H., Todorov, V., Kramer, B. K. & Kurtz, A. Angiotensin II inhibits renin gene transcription via the protein kinase C pathway. Pflugers Arch. 444, 499–505 (2002).
Klar, J. et al. Calcium inhibits renin gene expression by transcriptional and posttranscriptional mechanisms. Hypertension 46, 1340–1346 (2005).
Beutler, K. T. et al. Long-term regulation of ENaC expression in kidney by angiotensin II. Hypertension 41, 1143–1150 (2003).
Náray-Fejes-Tóth, A. & Fejes-Tóth, G. The sgk, an aldosterone-induced gene in mineralocorticoid target cells, regulates the epithelial sodium channel. Kidney Int. 57, 1290–1294 (2000).
Siragy, H. M. The angiotensin II type 2 receptor and the kidney. J. Renin Angiotensin Aldosterone Syst. 11, 33–36 (2010).
Matavelli, L. C. & Siragy, H. M. AT2 receptor activities and pathophysiological implications. J. Cardiovasc. Pharm. 65, 226–232 (2015).
Redublo Quinto, B. M. et al. Expression of angiotensin I-converting enzymes and bradykinin B-2 receptors in mouse inner medullary-collecting duct cells. Int. Immunopharmacol. 8, 254–260 (2008).
Kobori, H., Harrison-Bernard, L. M. & Navar, L. G. Expression of angiotensinogen mRNA and protein in angiotensin II-dependent hypertension. J. Am. Soc. Nephrol. 12, 431–439 (2001).
Prieto-Carrasquero, M. C. et al. Enhancement of collecting duct renin in angiotensin II-dependent hypertensive rats. Hypertension 44, 223–229 (2004).
Rohrwasser, A. et al. Renin and kallikrein in connecting tubule of mouse. Kidney Int. 64, 2155–2162 (2003).
HarrisonBernard, L. M., Navar, L. G., Ho, M. M., Vinson, G. P. & ElDahr, S. S. Immunohistochemical localization of ANGII AT(1) receptor in adult rat kidney using a monoclonal antibody. Am. J. Physiol. 273, F170–F177 (1997).
Gonzalez, A. A. et al. PKC-alpha-dependent augmentation of cAMP and CREB phosphorylation mediates the angiotensin II stimulation of renin in the collecting duct. Am. J. Physiol. Renal Physiol. 309, F880–F888 (2015).
Liu, L. et al. Increased renin excretion is associated with augmented urinary angiotensin II levels in chronic angiotensin II-infused hypertensive rats. Am. J. Physiol. Renal Physiol. 301, F1195–F1201 (2011).
Vonthun, A. M., Eldahr, S. S., Vari, R. C. & Navar, L. G. Differential expression of intrarenal renin-angiotensin system genes in angiotensin-II-induced and 2-kidney, one-clip (2K1C) hypertension. Hypertension 21, 601–601 (1993).
Peti-Peterdi, J., Warnock, D. G. & Bell, P. D. Angiotensin II directly stimulates ENaC activity in the cortical collecting duct via AT1 receptors. J. Am. Soc. Nephrol. 13, 1131–1135 (2002).
Mamenko, M., Zaika, O., Ilatovskaya, D. V., Staruschenko, A. & Pochynyuk, O. Angiotensin II increases activity of the epithelial Na+ channel (ENaC) in distal nephron additively to aldosterone. J. Biol. Chem 287, 660–671 (2012).
Mamenko, M. et al. Chronic angiotensin II infusion drives extensive aldosterone-independent epithelial Na+ channel activation. Hypertension 62, 1111–1122 (2013).
Sun, P., Yue, P. & Wang, W. H. Angiotensin II stimulates epithelial sodium channels in the cortical collecting duct of the rat kidney. Am. J. Physiol. Renal Physiol 302, F679–F687 (2012).
Lantelme, P. et al. Effects of dietary sodium and genetic background on angiotensinogen and renin in mouse. Hypertension 39, 1007–1014 (2002).
Shao, W., Seth, D. M., Prieto, M. C., Kobori, H. & Navar, L. G. Activation of the renin-angiotensin system by a low-salt diet does not augment intratubular angiotensinogen and angiotensin II in rats. Am. J. Physiol. Renal Physiol. 304, F505–F514 (2013).
Lee, Y. J. et al. Increased AQP2 targeting in primary cultured IMCD cells in response to angiotensin II through AT1 receptor. Am. J. Physiol. Renal Physiol. 292, F340–F350 (2007).
Stoos, B. A., Narayfejestoth, A., Carretero, O. A., Ito, S. & Fejestoth, G. Characterization of a mouse cortical collecting duct cell-line. Kidney Int. 39, 1168–1175 (1991).
Klingler, C. et al. Angiotensin II potentiates vasopressin-dependent cAMP accumulation in CHO transfected cells. Mechanisms of cross-talk between AT1A and V2 receptors. Cell Signal. 10, 65–74 (1998).
Matsusaka, T. et al. Liver angiotensinogen is the primary source of renal angiotensin II. J. Am. Soc. Nephrol. 23, 1181–1189 (2012).
Ingelfinger, J. R. et al. Rat proximal tubule cell line transformed with origin-defective SV40 DNA: autocrine ANGII feedback. Am. J. Physiol. 276, F218–F227 (1999).
Koizumi, M. et al. Podocyte injury augments intrarenal angiotensin ii generation and sodium retention in a megalin-dependent manner. Hypertension 74, 509–517 (2019).
Matsusaka, T. et al. Podocyte injury enhances filtration of liver-derived angiotensinogen and renal angiotensin II generation. Kidney Int. 85, 1068–1077 (2014).
Wu, C. H. et al. Antisense oligonucleotides targeting angiotensinogen: insights from animal studies. Biosci. Rep. 39, BSR20180201 (2019).
Mullick, A. E. et al. Blood pressure lowering and safety improvements with liver angiotensinogen inhibition in models of hypertension and kidney injury. Hypertension 70, 566–576 (2017).
Uijl, E. et al. Strong and sustained antihypertensive effect of small interfering RNA targeting liver angiotensinogen. Hypertension 73, 1249–1257 (2019).
Ye, F. et al. Angiotensinogen and megalin interactions contribute to atherosclerosis-brief report. Arterioscler. Thromb. Vasc. Biol. 39, 150–155 (2019).
Satou, R. et al. Blockade of sodium-glucose cotransporter 2 suppresses high glucose-induced angiotensinogen augmentation in renal proximal tubular cells. Am. J. Physiol. Renal Physiol. 318, F67–F75 (2020).
Reverte, V. et al. Urinary angiotensinogen increases in the absence of overt renal injury in high fat diet-induced type 2 diabetic mice. J. Diabetes Complications 34, 107448 (2020).
Navar, L. G., Kobori, H., Prieto, M. C. & Gonzalez-Villalobos, R. A. Intratubular renin-angiotensin system in hypertension. Hypertension 57, 355–362 (2011).
Navar, L. G., Prieto, M. C., Satou, R. & Kobori, H. Intrarenal angiotensin II and its contribution to the genesis of chronic hypertension. Curr. Opin. Pharmacol. 11, 180–186 (2011).
Satou, R., Penrose, H. & Navar, L. G. Inflammation as a regulator of the renin-angiotensin system and blood pressure. Curr. Hypertens. Rep. 20, 100 (2018).
Pohl, M. et al. Intrarenal renin angiotensin system revisited: role of megalin-dependent endocytosis along the proximal nephron. J. Biol. Chem. 285, 41935–41946 (2010).
Eladari, D., Chambrey, R. & Peti-Peterdi, J. A new look at electrolyte transport in the distal tubule. Annu. Rev. Physiol. 74, 325–349 (2012).
Batenburg, W. W. & Danser, A. J. Prorenin and the (pro)renin receptor: binding kinetics, signalling and interaction with aliskiren. J. Renin Angiotensin Aldosterone Syst. 9, 181–184 (2008).
Tamura, Y. et al. Water deprivation increases (Pro)renin receptor levels in the kidney and decreases plasma concentrations of soluble (Pro)renin receptor. Tohoku J. Exp. Med. 239, 185–192 (2016).
Li, Z. et al. (Pro)renin receptor is an amplifier of wnt/beta-catenin signaling in kidney injury and fibrosis. J. Am. Soc. Nephrol. 28, 2393–2408 (2017).
Fox, J., Guan, S., Hymel, A. A. & Navar, L. G. Dietary Na and Ace inhibition effects on renal tissue angiotensin-I and angiotensin-II and ACE activity in rats. Am. J. Physiol. 262, F902–F909 (1992).
Navar, L. G., Harrison-Bernard, L. M., Nishiyama, A. & Kobori, H. Regulation of intrarenal angiotensin II in hypertension. Hypertension 39, 316–322 (2002).
Harrison-Bernard, L. M., El-Dahr, S. S., O’Leary, D. F. & Navar, L. G. Regulation of angiotensin II type 1 receptor mRNA and protein in angiotensin II-induced hypertension. Hypertension 33, 340–346 (1999).
Kobori, H., Nishiyama, A., Abe, Y. & Navar, L. G. Enhancement of intrarenal angiotensinogen in Dahl salt-sensitive rats on high salt diet. Hypertension 41, 592–597 (2003).
Kamiyama, M. et al. Detailed localization of augmented angiotensinogen mRNA and protein in proximal tubule segments of diabetic kidneys in rats and humans. Int. J. Biol. Sci. 10, 530–542 (2014).
Mills, K. T. et al. Increased urinary excretion of angiotensinogen is associated with risk of chronic kidney disease. Nephrol. Dial. Transpl. 27, 3176–3181 (2012).
Ramkumar, N. et al. Collecting duct-specific knockout of renin attenuates angiotensin II-induced hypertension. Am. J. Physiol. Renal Physiol. 307, F931–F938 (2014).
Advani, A. et al. The (Pro) renin receptor site-specific and functional linkage to the vacuolar H+-ATPase in the kidney. Hypertension 54, 261–269 (2009).
Gonzalez, A. A., Luffman, C., Bourgeois, C. R., Vio, C. P. & Prieto, M. C. Angiotensin II-independent upregulation of cyclooxygenase-2 by activation of the (Pro)renin receptor in rat renal inner medullary cells. Hypertension 61, 443–449 (2013).
Breyer, R. M., Bagdassarian, C. K., Myers, S. A. & Breyer, M. D. Prostanoid receptors: subtypes and signaling. Annu. Rev. Pharmacol. Toxicol. 41, 661–690 (2001).
Hebert, R. L., Breyer, R. M., Jacobson, H. R. & Breyer, M. D. Functional and molecular aspects of prostaglandin-E receptors in the cortical collecting duct. Can. J. Physiol. Pharm. 73, 172–179 (1995).
Gonzalez, A. A. et al. Renal medullary cyclooxygenase-2 and (pro)renin receptor expression during angiotensin II-dependent hypertension. Am. J. Physiol. Renal Physiol. 307, F962–F970 (2014).
te Riet, L. et al. Deterioration of kidney function by the (pro)renin receptor blocker handle region peptide in aliskiren-treated diabetic transgenic (mRen2)27 rats. Am. J. Physiol. Renal Physiol. 306, F1179–F1189 (2014).
Salinas-Parra, N., Reyes-Martinez, C., Prieto, M. C. & Gonzalez, A. A. Prostaglandin E2 induces prorenin-dependent activation of (Pro)renin receptor and upregulation of cyclooxygenase-2 in collecting duct cells. Am. J. Med. Sci. 354, 310–318 (2017).
Wang, F. et al. Prostaglandin E-prostanoid4 receptor mediates angiotensin II-induced (pro)renin receptor expression in the rat renal medulla. Hypertension 64, 369–377 (2014).
Audoly, L. P. et al. Identification of specific EP receptors responsible for the hemodynamic effects of PGE2. Am. J. Physiol. 277, H924–H930 (1999).
Nüsing, R. M. et al. Dominant role of prostaglandin E2 EP4 receptor in furosemide-induced salt-losing tubulopathy: a model for hyperprostaglandin E syndrome/antenatal Bartter syndrome. J. Am. Soc. Nephrol. 16, 2354–2362 (2005).
Gonzalez, A. A. et al. Renal cyclooxygenase-2 expression and hemodynamic role during angiotensin II-dependent hypertension. Hypertension 62, A413 (2013).
Wang, F. et al. Antidiuretic action of collecting duct (Pro)renin receptor downstream of vasopressin and PGE2 receptor EP4. J. Am. Soc. Nephrol. 27, 3022–3034 (2016).
Chou, C. L., Rapko, S. I. & Knepper, M. A. Phosphoinositide signaling in rat inner medullary collecting duct. Am. J. Physiol. Renal Physiol. 274, F564–F572 (1998).
Gonzalez, A. A. & Prieto, M. C. Renin and the (pro)renin receptor in the renal collecting duct: role in the pathogenesis of hypertension. Clin. Exp. Pharmacol. Physiol. 42, 14–21 (2015).
Nguyen, G. et al. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J. Clin. Invest. 109, 1417–1427 (2002).
Song, R. et al. Prorenin receptor is critical for nephron progenitors. Dev. Biol. 409, 382–391 (2016).
Nguyen, G., Delarue, F., Berrou, J., Rondeau, E. & Sraer, J. D. Specific receptor binding of renin on human mesangial cells in culture increases plasminogen activator inhibitor-1 antigen. Kidney Int. 50, 1897–1903 (1996).
Uddin, M. N. et al. Non-proteolytic activation of prorenin: activation by (pro)renin receptor and its inhibition by a prorenin prosegment, “decoy peptide”. Front. Biosci. 13, 745–753 (2008).
Cruciat, C. M. et al. Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. Science 327, 459–463 (2010).
Ramkumar, N. et al. Collecting duct principal, but not intercalated, cell prorenin receptor regulates renal sodium and water excretion. Am. J. Physiol. Renal Physiol. 315, F607–F617 (2018).
Song, R. F., Preston, G., Ichihara, A. & Yosypiv, I. V. Deletion of the prorenin receptor from the ureteric bud causes renal hypodysplasia. PLoS ONE 8, e63835 (2013).
Zhang, L. et al. Inhibition of (pro)renin receptor contributes to renoprotective effects of angiotensin II type 1 receptor blockade in diabetic nephropathy. Front. Physiol. 8, 758 (2017).
Matavelli, L. C., Huang, J. Q. & Siragy, H. M. (Pro)renin receptor contributes to diabetic nephropathy by enhancing renal inflammation. Clin. Exp. Pharmacol. Physiol. 37, 277–282 (2010).
Ichihara, A., Kaneshiro, Y. & Suzuki, F. Prorenin receptor blockers: effects on cardiovascular complications of diabetes and hypertension. Expert Opin. Inv. Drug 15, 1137–1139 (2006).
Prieto, M. C. et al. Collecting duct prorenin receptor knockout reduces renal function, increases sodium excretion, and mitigates renal responses in ANGII-induced hypertensive mice. Am. J. Physiol. Renal Physiol. 313, F1243–F1253 (2017).
Gonzalez, A. A., Womack, J. P., Liu, L., Seth, D. M. & Prieto, M. C. Angiotensin II increases the expression of (Pro)renin receptor during low-salt conditions. Am. J. Med. Sci. 348, 416–422 (2014).
Huang, J. & Siragy, H. M. Sodium depletion enhances renal expression of (pro)renin receptor via cyclic GMP-protein kinase G signaling pathway. Hypertension 59, 317–323 (2012).
Quadri, S. & Siragy, H. M. (Pro)renin receptor contributes to regulation of renal epithelial sodium channel. J. Hypertens. 34, 486–494 (2016).
Clavreul, N., Sansilvestri-Morel, P., Magard, D., Verbeuren, T. J. & Rupin, A. (Pro)renin promotes fibrosis gene expression in HEK cells through a Nox4-dependent mechanism. Am. J. Physiol. Renal Physiol. 300, F1310–F1318 (2011).
Reyes-Martinez, C., Nguyen, Q. M., Kassan, M. & Gonzalez, A. A. (Pro)renin receptor-dependent induction of profibrotic factors is mediated by COX-2/EP4/NOX-4/Smad pathway in collecting duct cells. Front. Pharmacol. 10, 803 (2019).
Okamoto, C. et al. Excessively low salt diet damages the heart through activation of cardiac (pro) renin receptor, renin-angiotensin-aldosterone, and sympatho-adrenal systems in spontaneously hypertensive rats. PLoS ONE 12, e0189099 (2017).
Rong, R. et al. Expression of (pro)renin receptor and its upregulation by high salt intake in the rat nephron. Peptides 63, 156–162 (2015).
Su, J. et al. NF-κB-dependent upregulation of (pro)renin receptor mediates high-NaCl-induced apoptosis in mouse inner medullary collecting duct cells. Am. J. Physiol. Cell Physiol. 313, C612–C620 (2017).
Zhu, Q. & Yang, T. Enzymatic sources and physio-pathological functions of soluble (pro)renin receptor. Curr. Opin. Nephrol. Hypertens. 27, 77–82 (2018).
Cousin, C. et al. Soluble form of the (Pro)renin receptor generated by intracellular cleavage by furin is secreted in plasma. Hypertension 53, 1077–1082 (2009).
Yoshikawa, A. et al. The (pro)renin receptor is cleaved by ADAM19 in the Golgi leading to its secretion into extracellular space. Hypertens. Res. 34, 599–605 (2011).
Nakagawa, T. et al. Site-1 protease is required for the generation of soluble (pro)renin receptor. J. Biochem. 161, 369–379 (2017).
Morimoto, S. et al. Serum soluble (pro)renin receptor levels in patients with essential hypertension. Hypertens. Res. 37, 642–648 (2014).
Watanabe, N. et al. Prediction of gestational diabetes mellitus by soluble (pro)renin receptor during the first trimester. J. Clin. Endocrinol. Metab. 98, 2528–2535 (2013).
Watanabe, N. et al. Soluble (pro)renin receptor and blood pressure during pregnancy: a prospective cohort study. Hypertension 60, 1250–1256 (2012).
Lu, X. et al. Soluble (pro)renin receptor via beta-catenin enhances urine concentration capability as a target of liver X receptor. Proc. Natl Acad. Sci. USA 113, E1898–E1906 (2016).
Yang, K. T. et al. The soluble (Pro) renin receptor does not influence lithium-induced diabetes insipidus but does provoke beiging of white adipose tissue in mice. Physiol. Rep. 5, e13410 (2017).
Ichihara, A., Itoh, H. & Inagami, T. Critical roles of (pro)renin receptor-bound prorenin in diabetes and hypertension: sallies into therapeutic approach. J. Am. Soc. Hypertens. 2, 15–19 (2008).
Kaneshiro, Y. et al. Increased expression of cyclooxygenase-2 in the renal cortex of human prorenin receptor gene-transgenic rats. Kidney Int. 70, 641–646 (2006).
Quadri, S. S., Culver, S. & Siragy, H. M. Prorenin receptor mediates inflammation in renal ischemia. Clin. Exp. Pharmacol. Physiol. 45, 133–139 (2018).
Peters, J. et al. Lack of cardiac fibrosis in a new model of high prorenin hyperaldosteronism. Am. J. Physiol. Heart Circ. Physiol. 297, H1845–H1852 (2009).
Danser, A. H. The role of the (Pro)renin receptor in hypertensive disease. Am. J. Hypertens. 28, 1187–1196 (2015).
Nabi, A. H. et al. Binding properties of rat prorenin and renin to the recombinant rat renin/prorenin receptor prepared by a baculovirus expression system. Int. J. Mol. Med. 18, 483–488 (2006).
Siragy, H. M. & Huang, J. Q. Renal (pro)renin receptor upregulation in diabetic rats through enhanced angiotensin AT1 receptor and NADPH oxidase activity. Exp. Physiol. 93, 709–714 (2008).
Sun, Y. et al. Megalin: a novel endocytic receptor for prorenin and renin. Hypertension 75, 1242–1250 (2020).
Lee, J. W., Chou, C. L. & Knepper, M. A. Deep sequencing in microdissected renal tubules identifies nephron segment-specific transcriptomes. J. Am. Soc. Nephrol. 26, 2669–2677 (2015).
Roksnoer, L. C. et al. On the origin of urinary renin: a translational approach. Hypertension 67, 927–933 (2016).
Peruchetti, D. B., Silva-Aguiar, R. P., Siqueira, G. M., Dias, W. B. & Caruso-Neves, C. High glucose reduces megalin-mediated albumin endocytosis in renal proximal tubule cells through protein kinase B O-GlcNAcylation. J. Biol. Chem. 293, 11388–11400 (2018).
Kobori, H., Harrison-Bernard, L. M. & Navar, L. G. Enhancement of angiotensinogen expression in angiotensin II-dependent hypertension. Hypertension 37, 1329–1335 (2001).
Shao, W., Seth, D. M. & Navar, L. G. Augmentation of endogenous angiotension if levels in Val5-ANGII infused rats. J. Invest. Med. 56, 419–419 (2008).
Komlosi, P. et al. Angiotensin I conversion to angiotensin II stimulates cortical collecting duct sodium transport. Hypertension 42, 195–199 (2003).
Ramkumar, N., Ying, J., Stuart, D. & Kohan, D. E. Overexpression of renin in the collecting duct causes elevated blood pressure. Am. J. Hypertens. 26, 965–972 (2013).
Ramkumar, N. et al. Nephron-specific deletion of the prorenin receptor causes a urine concentration defect. Am. J. Physiol. Renal Physiol. 309, F48–F56 (2015).
Trepiccione, F. et al. Renal Atp6ap2/(Pro)renin receptor is required for normal vacuolar H+-ATPase function but not for the renin-angiotensin system. J. Am. Soc. Nephrol. 27, 3320–3330 (2016).
Ramkumar, N. et al. Renal tubular epithelial cell prorenin receptor regulates blood pressure and sodium transport. Am. J. Physiol. Renal Physiol. 311, F186–F194 (2016).
Gonzalez-Villalobos, R. A. et al. Intrarenal mouse renin-angiotensin system during ANGII-induced hypertension and ACE inhibition. Am. J. Physiol. Renal Physiol. 298, F150–F157 (2010).
Lu, X. et al. Activation of ENaC in collecting duct cells by prorenin and its receptor PRR: involvement of nox4-derived hydrogen peroxide. Am. J. Physiol. Renal Physiol. 310, F1243–F1250 (2016).
Humphreys, B. D. Mechanisms of renal fibrosis. Annu. Rev. Physiol. 80, 309–326 (2018).
Ichihara, A. et al. Contribution of nonproteolytically activated prorenin in glomeruli to hypertensive renal damage. J. Am. Soc. Nephrol. 17, 2495–2503 (2006).
Suzuki, F. et al. Human prorenin has “gate and handle” regions for its non-proteolytic activation. J. Biol. Chem. 278, 22217–22222 (2003).
Nabi, A. H. M. N. & Suzuki, F. Biochemical properties of renin and prorenin binding to the (pro)renin receptor. Hypertens. Res. 33, 91–97 (2009).
Kaneshiro, Y. et al. Slowly progressive, angiotensin ii-independent glomerulosclerosis in human (Pro)renin receptor-transgenic rats. J. Am. Soc. Nephrol. 18, 1789–1795 (2007).
Muller, D. N. et al. (Pro) renin receptor peptide inhibitor “handle-region” peptide does not affect hypertensive nephrosclerosis in Goldblatt rats. Hypertension 51, 676–681 (2008).
Batenburg, W. W. et al. The (pro)renin receptor blocker handle region peptide upregulates endothelium-derived contractile factors in aliskiren-treated diabetic transgenic (mREN2)27 rats. J. Hypertens. 31, 292–302 (2013).
Li, W. et al. Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension. Hypertension 65, 352–361 (2015).
Roksnoer, L. C. W. et al. Urinary markers of intrarenal renin-angiotensin system activity in vivo. Curr. Hypertens. Rep. 15, 81–88 (2013).
Sun, Y., Lu, X. & Danser, A. H. J. Megalin: a novel determinant of renin-angiotensin system activity in the kidney? Curr. Hypertens. Rep. 22, 30 (2020).
Roksnoer, L. C. W. et al. Methodologic issues in the measurement of urinary renin. Clin. J. Am. Soc. Nephrol. 9, 1163–1167 (2014).
Acknowledgements
The authors’ work is funded by the NIH through the CoBRE, P30GM-103337 grant to L.G.N; and the DK104375, 1U54GM104940 and UL1TR001417 grants to M.C.P. The authors thank Nancy Busija (Department of Pharmacology, Tulane University, USA) for editorial assistance with the manuscript before submission.
Author information
Authors and Affiliations
Contributions
M.C.P., A.A.G. and B.V. researched data for the article. M.C.P., A.A.G. and L.G.N. participated in the discussion of the content, writing and revising the article and/or editing the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Peer review information
Nature Reviews Nephrology thanks the anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Glossary
- 2K1C Goldblatt hypertension
-
The two-kidney, one-clip (2K1C) Goldblatt hypertensive rat is an experimental model for studying renovascular hypertension, whereby one renal artery is clipped to decrease renal blood flow, and the other kidney remains unaffected.
- Antisense oligonucleotides
-
Short DNA or RNA molecules that regulate gene expression by blocking the transcription or translation of target genes.
Rights and permissions
About this article
Cite this article
Prieto, M.C., Gonzalez, A.A., Visniauskas, B. et al. The evolving complexity of the collecting duct renin–angiotensin system in hypertension. Nat Rev Nephrol 17, 481–492 (2021). https://doi.org/10.1038/s41581-021-00414-6
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41581-021-00414-6