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Newly Stemming Functions of Macula Densa–Derived Prostanoids

2015; Lippincott Williams & Wilkins; Volume: 65; Issue: 5 Linguagem: Inglês

10.1161/hypertensionaha.115.04739

ISSN

1524-4563

Autores

János Peti‐Peterdi,

Tópico(s)

Hormonal Regulation and Hypertension

Resumo

HomeHypertensionVol. 65, No. 5Newly Stemming Functions of Macula Densa–Derived Prostanoids Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBNewly Stemming Functions of Macula Densa–Derived Prostanoids János Peti-Peterdi János Peti-PeterdiJános Peti-Peterdi From the Departments of Physiology and Biophysics, and Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles. Originally published16 Mar 2015https://doi.org/10.1161/HYPERTENSIONAHA.115.04739Hypertension. 2015;65:987–988Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2015: Previous Version 1 See related article, pp 1047–1054Macula densa (MD) cells are chief cells within the kidney, playing key sensory and regulatory functions in the maintenance of body fluid, electrolyte homeostasis, and blood pressure. MD cells are strategically positioned in the distal nephron at the entrance of the glomerulus as the tubular component of the juxtaglomerular apparatus (JGA), an important renal anatomic site that controls renal hemodynamics, glomerular filtration, and renin release (renin–angiotensin system activation). Despite their importance, MD cells have been a mysterious renal cell type mainly because their low number (only ≈20 cells per nephron) and relative inaccessibility make them difficult to study. Therefore, our knowledge of the MD is limited to the traditional functions of these cells: the sensing of variations in the distal tubular fluid microenvironment (tubular salt, metabolites, and flow) and the generation and release of paracrine mediators for tubulovascular cross talk that controls afferent arteriole vasoconstriction (tubuloglomerular feedback) and renin secretion.1–4 Tubular salt sensing by the MD involves apical NaCl transport via the furosemide-sensitive Na:2Cl:K cotransporter (NKCC2), which is the primary NaCl entry mechanism in these cells. In fact, a classic hallmark of MD-mediated renin release is its effective stimulation by furosemide or other loop diuretics.1,2 The downstream elements of MD-mediated renin release signaling include the low tubular salt-induced and NKCC2-mediated activation of p38, extracellular-regulated kinase 1/2, mitogen-activated protein kinases, cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase, and the synthesis and release of prostaglandin E2 (PGE2) by these cells.5 PGE2 is the classic paracrine mediator of MD-mediated renin release, acting mainly on the EP4 receptor subtype of PGE2 receptors on juxtaglomerular renin cells (Figure).2Download figureDownload PowerPointFigure. Schematic illustration of the traditional and new functions of macula densa (MD)–derived prostaglandin E2 (PGE2). The sensing of reduced tubular (NaCl) via the furosemide-sensitive Na:2Cl:K (NKCC2) cotransporter leads to p38 and extracellular-regulated kinase 1/2 (ERK1/2; mitogen-activated protein kinase) signaling, increased PGE2 synthesis, and release via cycloxygenase-2 (COX-2) and microsomal PGE synthase (mPGES) activation in MD cells. The paracrine action of MD-derived PGE2 causes renin release from juxtaglomerular (JG) renin cells (JGC) via the EP4 receptor (classic function). The newly emerging function of this MD/PGE2/EP4 axis is the recruitment of new renin cells into the JG apparatus (JGA) via the activation of CD44+ mesenchymal stem cell–like cells in the renal interstitium and their migration toward the JGA, and their differentiation into renin-producing JGCs. AA indicates afferent arteriole; EA, efferent arteriole; and G, glomerulus.The most important and immediate MD partner cell in the JGA, the renin-producing juxtaglomerular cell, has received considerable attention in the past few years. A variety of stress stimuli that threaten body fluid and electrolyte homeostasis increase circulating renin and activate the renin–angiotensin system, one of the first lines of systemic defense mechanisms, by increasing the number of renin-expressing and releasing juxtaglomerular cells in the terminal part of the afferent arteriole (JGA). According to the prevailing renal physiology paradigm, juxtaglomerular cell recruitment involves dedifferentiation and re-expression of renin in afferent arteriole vascular smooth muscle cells that belong to the renin cell lineage.6,7 However, this classic paradigm of juxtaglomerular cell recruitment was challenged recently by the demonstration that CD44+ mesenchymal stem cell–like cells exist in the adult kidney are recruited to the juxtaglomerular area and differentiate into renin cells in response to loss of body fluid and salt.8 Another study showed that cells of the renin lineage are progenitors of podocytes and parietal epithelial cells in glomerular disease and may enhance glomerular regeneration.9 These studies opened a new era in renin cell research and established new links between renal stem/progenitor cells, renal physiology, and kidney disease that involve the renin cell. One of the many exciting questions stemming from these studies is what controls renal stem cell recruitment to the JGA?In this issue, Yang et al10 report their new study that addressed this question. As a logical extension of their recent work mentioned above (about CD44+ mesenchymal cell recruitment to the JGA8), the same group of investigators hypothesized that chronic sodium deprivation stimulates renal CD44+ cell activation, migration, and differentiation into juxtaglomerular renin cells via MD-derived PGE2. First, they applied an in vitro approach and cocultured isolated CD44+ cells with a MD cell line. Lowering the NaCl content of the culture medium induced PGE2 production by MD cells and the migration of CD44+ cells, the effect of which was inhibited by the pharmacological blockade of COX-2 or EP4 receptor.10 Also, the addition of PGE2 to CD44+ cells increased cell migration and induced renin expression via the EP4 receptor.10 Second, the investigators used an in vivo experimental model and found that the recruitment of renal CD44+ cells to the JGA, which was activated by dietary sodium restriction and furosemide treatment, was attenuated in wild-type mice by treatment with the COX-2 inhibitor rofecoxib and by EP4 receptor deficiency.10 Altogether, this study provides new insights into the physiologically and pathologically important mechanism of juxtaglomerular cell recruitment and identifies new key players in this process: MD control of a PGE2/EP4 signaling axis and renal CD44+ mesenchymal stem cell–like cells as effectors. It should be noted that although the in vitro cell data strongly suggest the role of MD cells, MD cell specificity and origin of PGE2 were not unequivocally demonstrated in the present in vivo studies. Future experiments need to further clarify the role of MD-derived prostanoids and likely other factors in renal stem cell–mediated juxtaglomerular cell recruitment in vivo. Regardless, the present findings by Yang et al10 will significantly advance the fields of renal physiology and renal stem cells.Because the importance of MD-derived PGE2 in renin release is well established, it makes perfect sense that the MD, via PGE2/EP4 signaling to renal stem cells, controls juxtaglomerular cell recruitment as well. The strategic anatomic localization of the small MD cell plaque at the vascular entrance of the glomerulus and the MD-specific expression of COX-2 and microsomal prostaglandin E synthase that provides a point source of PGE2 are consistent with the development of a PGE2 dose gradient in the renal cortex that activates and directs the migration of renal stem cells toward the JGA epicenter. The findings of several earlier studies are supportive of this new function of MD-derived prostanoids acting on stem cells. For example, the paracrine action of PGE2 via the EP4 receptor on the target cell is a well-established mechanism for stem and progenitor cell trafficking in many tissues.11 Also, COX-2 and its products are known to be important factors in embryonic nephrogenesis. Partial genetic knockout or chemical inhibitors of COX-2 were shown to inhibit glomerulogenesis.12 It is highly anticipated that future studies will shed more light on these newly stemming functions of the mysterious MD cells.Sources of FundingThis work was supported by National Institute of Health grants DK64324 and DK100944 and by the American Heart Association grant 15GRNT23040039.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to János Peti-Peterdi, Zilkha Neurogenetic Institute, ZNI335, University of Southern California, 1501 San Pablo St, Los Angeles, CA 90033. E-mail [email protected]References1. Peti-Peterdi J, Harris RC.Macula densa sensing and signaling mechanisms of renin release.J Am Soc Nephrol. 2010; 21:1093–1096. doi: 10.1681/ASN.2009070759.CrossrefMedlineGoogle Scholar2. Schnermann J, Briggs JP.Synthesis and secretion of renin in mice with induced genetic mutations.Kidney Int. 2012; 81:529–538. doi: 10.1038/ki.2011.451.CrossrefMedlineGoogle Scholar3. Sipos A, Vargas S, Peti-Peterdi J.Direct demonstration of tubular fluid flow sensing by macula densa cells.Am J Physiol Renal Physiol. 2010; 299:F1087–F1093. doi: 10.1152/ajprenal.00469.2009.CrossrefMedlineGoogle Scholar4. Vargas SL, Toma I, Kang JJ, Meer EJ, Peti-Peterdi J.Activation of the succinate receptor GPR91 in macula densa cells causes renin release.J Am Soc Nephrol. 2009; 20:1002–1011. doi: 10.1681/ASN.2008070740.CrossrefMedlineGoogle Scholar5. Peti-Peterdi J, Komlosi P, Fuson AL, Guan Y, Schneider A, Qi Z, Redha R, Rosivall L, Breyer MD, Bell PD.Luminal NaCl delivery regulates basolateral PGE2 release from macula densa cells.J Clin Invest. 2003; 112:76–82. doi: 10.1172/JCI18018.CrossrefMedlineGoogle Scholar6. Castrop H, Höcherl K, Kurtz A, Schweda F, Todorov V, Wagner C.Physiology of kidney renin.Physiol Rev. 2010; 90:607–673. doi: 10.1152/physrev.00011.2009.CrossrefMedlineGoogle Scholar7. Sequeira López ML, Pentz ES, Nomasa T, Smithies O, Gomez RA.Renin cells are precursors for multiple cell types that switch to the renin phenotype when homeostasis is threatened.Dev Cell. 2004; 6:719–728.CrossrefMedlineGoogle Scholar8. Wang H, Gomez JA, Klein S, Zhang Z, Seidler B, Yang Y, Schmeckpeper J, Zhang L, Muramoto GG, Chute J, Pratt RE, Saur D, Mirotsou M, Dzau VJ.Adult renal mesenchymal stem cell-like cells contribute to juxtaglomerular cell recruitment.J Am Soc Nephrol. 2013; 24:1263–1273. doi: 10.1681/ASN.2012060596.CrossrefMedlineGoogle Scholar9. Pippin JW, Sparks MA, Glenn ST, Buitrago S, Coffman TM, Duffield JS, Gross KW, Shankland SJ.Cells of renin lineage are progenitors of podocytes and parietal epithelial cells in experimental glomerular disease.Am J Pathol. 2013; 183:542–557. doi: 10.1016/j.ajpath.2013.04.024.CrossrefMedlineGoogle Scholar10. Yang Y, Gomez JA, Herrera M, et al. Salt restriction leads to activation of adult renal mesenchymal stromal cell–like cells via prostaglandin E2 and E-prostanoid receptor 4.Hypertension. 2015; 65:1047–1054. doi: 10.1161/HYPERTENSIONAHA.114.04611.LinkGoogle Scholar11. Hoggatt J, Singh P, Sampath J, Pelus LM.Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation.Blood. 2009; 113:5444–5455. doi: 10.1182/blood-2009-01-201335.CrossrefMedlineGoogle Scholar12. Kömhoff M, Wang JL, Cheng HF, Langenbach R, McKanna JA, Harris RC, Breyer MD.Cyclooxygenase-2-selective inhibitors impair glomerulogenesis and renal cortical development.Kidney Int. 2000; 57:414–422. doi: 10.1046/j.1523-1755.2000.00861.x.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Winter W and Harris N (2021) Laboratory evaluation of endocrine hypertension Handbook of Diagnostic Endocrinology, 10.1016/B978-0-12-818277-2.00011-X, (391-447), . Cowley A (2021) Salt intake and the dance of the macula densa cells, American Journal of Physiology-Renal Physiology, 10.1152/ajprenal.00051.2021, 320:3, (F375-F377), Online publication date: 1-Mar-2021. Lorenzi T, Graciotti L, Sagrati A, Reguzzoni M, Protasoni M, Minardi D, Milanese G, Cremona O, Fabri M and Morroni M (2020) Normal human macula densa morphology and cell turnover: A histological, ultrastructural, and immunohistochemical investigation, The Anatomical Record, 10.1002/ar.24465, 303:11, (2904-2916), Online publication date: 1-Nov-2020. Gomez R and Sequeira-Lopez M (2018) Renin cells in homeostasis, regeneration and immune defence mechanisms, Nature Reviews Nephrology, 10.1038/nrneph.2017.186, 14:4, (231-245), Online publication date: 1-Apr-2018. Cangiotti A, Lorenzi T, Zingaretti M, Fabri M and Morroni M (2018) Polarized Ends of Human Macula Densa Cells: Ultrastructural Investigation and Morphofunctional Correlations, The Anatomical Record, 10.1002/ar.23759, 301:5, (922-931), Online publication date: 1-May-2018. Sharma M, Sharma R, McCarthy E, Savin V and Srivastava T (2017) Hyperfiltration-associated biomechanical forces in glomerular injury and response: Potential role for eicosanoids, Prostaglandins & Other Lipid Mediators, 10.1016/j.prostaglandins.2017.01.003, 132, (59-68), Online publication date: 1-Sep-2017. GÜRCÜ B and KARAÇALI S (2021) Differentiation of Juxtaglomerular Apparatus Cells in Developing Nephrons in BALB /c Type Mouse Embryos, Celal Bayar Üniversitesi Sağlık Bilimleri Enstitüsü Dergisi, 10.34087/cbusbed.827212 May 2015Vol 65, Issue 5 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.115.04739PMID: 25776068 Originally publishedMarch 16, 2015 PDF download Advertisement SubjectsHypertension

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