SCIENCE IN RENAL MEDICINE www.jasn.org Macula Densa Sensing and Signaling Mechanisms of Renin Release Ja´nos Peti-Peterdi* and Raymond C. Harris† *Departments of Physiology and Biophysics and Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California; and †Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee ABSTRACT 8 Macula densa cells in the distal nephron, according to the classic paradigm, are salt release of PGE2. PGE2 acts on EP2 and sensors that generate paracrine chemical signals in the juxtaglomerular apparatus EP4 receptors in juxtaglomerular cells to control vital kidney functions, including renal blood flow, glomerular filtration, and causes renin release (Figure 1B).10 In and renin release. Renin is the rate-limiting step in the activation of the renin- addition to COX-2-derived prostaglan- angiotensin system, a key modulator of body fluid homeostasis. Here, we discuss dins, the neural isoform of nitric oxide recent advances in understanding macula densa sensing and suggest these cells, in synthases, which is selectively expressed addition to salt, also sense various chemical and metabolic signals in the tubular in macula densa cells,11 is critical in the environment that directly trigger renin release. tubuloglomerular feedback and renin signaling cascade.2,12,13 The paracrine J Am Soc Nephrol 21: 1093–1096, 2010. doi: 10.1681/ASN.2009070759 chemical signals of macula densa-medi- ated inhibition of renin release include ATP and adenosine.1–3,14 The juxtaglomerular apparatus in the renal juxtaglomerular apparatus-glomerular Besides the well-known NKCC2 co- cortex represents a major structural com- complex. These cells play a pivotal role in transporter, macula densa cells possess an ponent of the renin-angiotensin system sensing changes in tubular fluid composi- apical Naϩ:Hϩ exchanger (NHE), identi- and is one of the most important regula- tion, generating and sending signals to the fied as the NHE2 isoform,15 that partici- tory sites of renal salt and water conserva- juxtaglomerular apparatus that control re- pates in Naϩ transport as well as the regu- tion and BP maintenance. The juxtaglo- nal blood flow and GFR through tubulo- lation of cell volume and intracellular merular apparatus consists of a tubular glomerular feedback and renin release.1–3 pH.15,16 A recent study found that NHE2 is component, the macula densa, the extra- Tubular salt sensing by the macula densa also involved in macula densa salt-sensing glomerular mesangium, and a vascular el- involves apical NaCl transport mecha- and renin control, and suggests that mac- ement that involves the terminal parts of nisms, including the furosemide-sensitive ula densa cell shrinkage is the likely cellular the afferent arteriole containing renin-pro- Naϩ:2ClϪ:Kϩ cotransporter (NKCC2), signal that activates renin release signal- ducing juxtaglomerular cells. Two major which is the primary NaCl entry mecha- ing.17 Renal tissue renin activity and regulatory functions are performed by the nism. In fact, a classic hallmark of tubulo- plasma renin concentrations are both ele- juxtaglomerular apparatus: the high distal glomerular feedback and renin release is vated 3-fold and 2-fold, respectively, in tubular [NaCl]-induced afferent arteriolar their effective inhibition or stimulation, re- NHE2Ϫ/Ϫ mice compared with wild vasoconstriction (tubuloglomerular feed- spectively, by furosemide or other loop di- back) and the low tubular [NaCl]-induced uretics.1–4 renin release.1 Macula densa cells are stra- The downstream elements of macula Published online ahead of print. Publication date tegically positioned in the juxtaglomerular densa-mediated signaling of renin re- available at www.jasn.org. apparatus with their apical membrane ex- lease include, at least, the low tubular Correspondence: Dr. J. Peti-Peterdi, 1501 San Pablo Street, ZNI 335, Los Angeles, CA 90033. posed to the tubular fluid, whereas their salt-induced and NKCC2-mediated acti- Phone: 323-442-4337; Fax: 323-442-4466; E-mail: basilar aspects are in contact with cells of vation of p38 and extracellular-regulated [email protected]. Dr. R. C. Harris, Division of Ne- the mesangium and the afferent arteriole kinase 1/2 (ERK1/2) mitogen-activated phrology, Vanderbilt University School of Medicine, MCN C3121, 1161 21st Street South, Nashville, TN (Figure 1A). protein (MAP) kinases, cyclooxygen- 37232. Phone: 615-322-2150; Fax: 615-343-2675; The macula densa plaque is a unique ase-2 (COX-2) and microsomal prosta- E-mail: [email protected] group of 15 to 20 cells located at the end of glandin E synthase (mPGES) in the mac- Copyright © 2010 by the American Society of the cortical thick ascending limb forming a ula densa,4–9 and the synthesis and Nephrology J Am Soc Nephrol 21: 1093–1096, 2010 ISSN : 1046-6673/2107-1093 1093 SCIENCE IN RENAL MEDICINE www.jasn.org Macula densa Sympathetic A B mechanism nervous system Mesangium Macula β-adrenergic densa cells Renin nerves granular Afferent arteriole cells endothelium & Tubular Na smooth muscle salt 2Cl COX-2 K mPGES sensing PGE2 cAMP Na 2+ Local baroreflex ERK1/2 NO Ca H p38 Metabolic sensing S nNOS ANP GPR91 Local hormones ANGII Figure 1. Fluorescence microscopic image (A) and schematic (B) of the juxtaglomerular apparatus (juxtaglomerular apparatus). (A) A multiphoton confocal fluorescence image of the juxtaglomerular apparatus in the intact rat kidney in vivo showing the afferent (AA) and efferent arterioles (EA) and cortical thick ascending limb (cTAL) containing the macula densa. Original magnification, ϫ250. Renin granular content in juxtaglomerular cells under the macula densa is labeled green using quinacrine as described before.34 (B) The main control mechanisms of renin release and elements of the macula densa sensing and signaling apparatus. Macula densa cells can sense variations in tubular fluid composition, including salt content and metabolites such as succinate. Salt is sensed via the NKCC2 and NHE2, whereas tubular succinate triggers the metabolic receptor GPR91 at the luminal plasma membrane. Signal transduction includes activation of MAP kinases p38 and pERK1/2, PGE2 synthesis through COX-2, and mPGES. PGE2 via paracrine signaling causes increased renin synthesis and release from adjacent juxtaglomerular cells and activation of the renin-angiotensin system (RAS). S, succinate; nNOS, neural nitric oxide synthase. Ϫ Ϫ type.17 NHE2 / mice also exhibit a signif- limiting step of renin-angiotensin system stimulates renin release.18 The most im- icantly increased renal expression of corti- activation that is precisely controlled by portant inhibitory mechanism of renin cal COX-2 and mPGES, indicating macula several mechanisms (Figure 1B). Reduc- synthesis and release is elevations in jux- densa-specific mechanisms responsible for tions in extracellular fluid volume taglomerular cell calcium concentra- the increased renin content.17 Importantly, through four major mechanisms: low re- tion.19 This effect of calcium is rather un- pharmacologic inhibition or genetic dele- nal perfusion pressure (local baroreflex usual because calcium usually facilitates tion of NHE2 activates MAP kinases mechanism); activation of the sympa- exocytosis in other cells and systems. Its ERK1/2, causing activation of the PGE2 thetic nervous system; reductions in inhibitory effect on renin secretion has synthetic enzymes COX-2 and mPGES. macula densa salt transport; and reduced been coined the “calcium paradox of re- Hypertonicity-induced cell shrinkage, but levels of locally acting hormones (such as nin release,” and this is because of the not cell acidification, also triggers ERK1/2 angiotensin II and atrial naturetic pep- expression of calcium-inhibited adenyl- activation in macula densa cells,17 suggest- tide) ultimately increase circulating and ate cyclase, AC5, in juxtaglomerular ing it is the low macula densa cell volume interstitial renin levels that lead to en- cells. rather than low intracellular pH that acti- hanced generation of angiotensin pep- COX-2, the source of macula densa- vates macula densa renin-release signal. In- tides.18 Angiotensin II, one of the most derived prostaglandins mediating renin terestingly, macula densa cells also possess potent vasoconstrictors and major prod- expression and release by the juxtaglo- ϩ ϩ a basolateral Na :H exchanger, NHE4.15 ucts of the renin-angiotensin system, merular apparatus, is present at low but This polarized NHE2/NHE4 configura- helps re-establish fluid balance and nor- detectable levels in the macula densa un- tion in the macula densa is unique and dis- mal BP by actions on multiple organs der normal homeostatic conditions.5 In- tinct from the usual NHE3/NHE1 arrange- providing blood vessel constriction, in- duction of a high-renin state by imposi- ment in other nephron segments, further creased renal and gastrointestinal salt tion of a salt-deficient diet, angiotensin- suggesting that NHEs play a combined role and water reabsorption, and aldosterone converting enzyme inhibition, diuretic in macula densa cell function.15 production by the adrenal gland. administration, or experimental reno- On a cellular and molecular level, vascular hypertension all significantly in- prostaglandins (mainly PGI2 and PGE2) crease COX-2 expression by the macula THE CLASSIC VIEW OF RENIN and nitric oxide mediate paracrine re- densa.20–23 Alterations in macula densa CONTROL IN THE nin-release signals in the juxtaglomeru- COX-2