From the departments of Physiology and also Biophysics, and also Medicine, Zilkha Neurogenetic Institute, college of southern California, Los Angeles.
Originally published16 Mar 2015https://doi.org/10.1161/HYPERTENSIONAHA.115.04739Hypertension. 2015;65:987–988

See related article, pp 1047–1054

Macula densa (MD) cells space chief cell within the kidney, playing vital sensory and regulatory functions in the maintenance of human body fluid, electrolyte homeostasis, and also blood pressure. MD cells room strategically positioned in the distal nephron at the entrance of the glomerulus as the tubular component of the juxtaglomerular device (JGA), an important renal anatomic site that controls renal hemodynamics, glomerular filtration, and also renin relax (renin–angiotensin mechanism activation). Regardless of their importance, MD cells have been a mysterious renal cell form mainly because their short number (only ≈20 cells every nephron) and relative inaccessibility do them challenging to study. Therefore, our knowledge of the MD is minimal to the classic functions of these cells: the sensing of sport in the distal tubular liquid microenvironment (tubular salt, metabolites, and flow) and the generation and also release that paracrine mediators because that tubulovascular cross talk that controls afferent arteriole vasoconstriction (tubuloglomerular feedback) and renin secretion.1–4 Tubular salt sensing by the MD entails apical NaCl transport via the furosemide-sensitive Na:2Cl:K cotransporter (NKCC2), which is the main NaCl entry device in these cells. In fact, a classic hallmark of MD-mediated renin relax is its reliable stimulation through furosemide or other loop diuretics.1,2 The downstream elements of MD-mediated renin relax signaling encompass the low tubular salt-induced and NKCC2-mediated activation the p38, extracellular-regulated kinase 1/2, mitogen-activated protein kinases, cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase, and also the synthesis and release the prostaglandin E2 (PGE2) by this cells.5 PGE2 is the standard paracrine mediator of MD-mediated renin release, acting mainly on the EP4 receptor subtype that PGE2 receptors on juxtaglomerular renin cells (Figure).2

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Figure.

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Schematic illustration that 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 leader to p38 and also extracellular-regulated kinase 1/2 (ERK1/2; mitogen-activated protein kinase) signaling, enhanced PGE2 synthesis, and also release via cycloxygenase-2 (COX-2) and also microsomal PGE synthase (mPGES) activation in MD cells. The paracrine action of MD-derived PGE2 reasons renin relax from juxtaglomerular (JG) renin cell (JGC) via the EP4 receptor (classic function). The recently emerging function of this MD/PGE2/EP4 axis is the recruitment of new renin cells into the JG device (JGA) via the activation of CD44+ mesenchymal stem cell–like cell in the renal interstitium and their migration toward the JGA, and also their differentiation into renin-producing JGCs. AA suggests afferent arteriole; EA, efferent arteriole; and G, glomerulus.

The many important and also immediate MD partner cell in the JGA, the renin-producing juxtaglomerular cell, has actually received significant attention in the past few years. A range of anxiety stimuli that threaten human body fluid and electrolyte homeostasis rise circulating renin and also activate the renin–angiotensin system, one of the first lines the systemic defense mechanisms, by raising the variety of renin-expressing and also releasing juxtaglomerular cell in the terminal component of the afferent arteriole (JGA). Follow to the prevailing renal physiology paradigm, juxtaglomerular cell recruitment involves dedifferentiation and re-expression the renin in afferent arteriole vascular smooth muscle cells the belong come the renin cell lineage.6,7 However, this classic paradigm the juxtaglomerular cell recruitment was challenged recently by the demonstration that CD44+ mesenchymal stem cell–like cell exist in the adult kidney room recruited come the juxtaglomerular area and differentiate right into renin cells in solution to loss of body fluid and salt.8 another study confirmed that cells of the renin family tree are progenitors the podocytes and also parietal epithelial cell in glomerular an illness and may enhance glomerular regeneration.9 this studies opened up a brand-new era in renin cell research and established brand-new links between renal stem/progenitor cells, renal physiology, and kidney an illness that involve the renin cell. Among the numerous exciting inquiries stemming from these researches is what controls renal stem cell recruitment to the JGA?

In this issue, Yang et al10 report their new study that addressed this question. Together a logical extension of their recent work-related mentioned above (about CD44+ mesenchymal cabinet recruitment come the JGA8), the same group of investigators hypothesized the chronic sodium deprivation stimulates renal CD44+ cabinet activation, migration, and also differentiation right into juxtaglomerular renin cell via MD-derived PGE2. First, they applied an in vitro approach and also cocultured diverted CD44+ cells v a MD cell line. Lowering the NaCl contents of the society medium induced PGE2 manufacturing by MD cells and also the migrate of CD44+ cells, the result of which was inhibited through the pharmacological blockade of COX-2 or EP4 receptor.10 Also, the addition of PGE2 to CD44+ cells increased cell migration and also induced renin expression via the EP4 receptor.10 Second, the investigators provided an in vivo speculative model and found that the recruitment that renal CD44+ cells to the JGA, i beg your pardon was triggered by dietary sodium restriction and furosemide treatment, to be attenuated in wild-type mouse by treatment with the COX-2 inhibitor rofecoxib and also by EP4 receptor deficiency.10 Altogether, this study provides new insights right into the physiologically and also pathologically necessary mechanism of juxtaglomerular cabinet recruitment and identifies new crucial players in this process: MD control of a PGE2/EP4 signaling axis and renal CD44+ mesenchymal stem cell–like cells as effectors. It have to be noted that although the in vitro cabinet data strongly indicate the function of MD cells, MD cabinet specificity and also origin the PGE2 were not unequivocally prove in the current in vivo studies. Future experiments require to more clarify the role of MD-derived prostanoids and likely other factors in renal stem cell–mediated juxtaglomerular cabinet recruitment in vivo. Regardless, the current findings by Yang et al10 will significantly breakthrough the areas of renal physiology and renal stem cells.

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Because the prominence of MD-derived PGE2 in renin relax is fine established, it renders perfect feeling that the MD, via PGE2/EP4 signaling come renal stem cells, controls juxtaglomerular cabinet recruitment as well. The strategic anatomic localization of the small MD cell plaque at the vascular enntrance gate of the glomerulus and also the MD-specific expression of COX-2 and also microsomal prostaglandin E synthase that gives a point source of PGE2 are continuous with the development of a PGE2 dose gradient in the renal cortex the activates and also directs the migrate of renal stem cells toward the JGA epicenter. The findings of several previously studies are supportive that this brand-new function that MD-derived prostanoids acting on stem cells. Because that example, the paracrine action of PGE2 via the EP4 receptor ~ above the target cabinet is a well-established device for stem and progenitor cabinet trafficking in many tissues.11 Also, COX-2 and its products are known to it is in important factors in embryonic nephrogenesis. Partial genetic knockout or chemical inhibitors that COX-2 were displayed to inhibit glomerulogenesis.12 it is extremely anticipated the future researches will shed much more light ~ above these recently stemming attributes of the secret MD cells.