Commentary for “human kidney pericytes produce renin”
Authors: Armin Kurtz
Journal: Kidney International (2016)

Renin-secreting cells of the kidney display several particularities, including their intrarenal localization in the fetal and in the adult kidney, their ultrastructure, and the mode by which they secrete renin into circulation to trigger the activity of the renin-angiotensin-aldosterone system. The cell type from which renin cells differentiate has long been subject to speculation. The paper by Stefanska et al. now strongly suggests that renin cells are or derive from pericytes. Renin-secreting cells of the kidney display several particularities, including their intrarenal localization in the fetal and in the adult kidney, their ultrastructure, and the mode by which they secrete renin into circulation to trigger the activity of the renin-angiotensin-aldosterone system. The cell type from which renin cells differentiate has long been subject to speculation. The paper by Stefanska et al. now strongly suggests that renin cells are or derive from pericytes. Renin-secreting cells of the kidney are the starters and the sustaining motors of the systemic renin-angiotensin-aldosterone system. Their almost exclusive localization in the juxtaglomerular region has coined the term juxtaglomerular cells for renal renin-producing cells of adult kidneys. The cells have a cuboid shape and they impress by their striking ultrastructural morphology as the cells contain numerous electron-dense vesicles. These vesicles are lysosome-related organelles in which newly synthesized prorenin is taken up and proteolytically cleaved to renin. Renin is released from these vesicles by cyclic adenosine monophosphate–driven compound exocytosis. During kidney development, renin-producing cells arise rather early from the FoxD1-positive cell lineage of the metanephric mesenchyme.1Sequeira Lopez M.L. Gomez R.A. Development of the renal arterioles.J Am Soc Nephrol. 2011; 22: 2156-2165Crossref PubMed Scopus (105) Google Scholar During kidney differentiation, renin-expressing cells are associated with wall cells of the developing preglomerular arteriolar vessel tree, which results from sprouting angiogenesis. Renin expression follows a specific spatiotemporal pattern, in the way the renin expression is strongest in newly developing arterioles, but it ceases and finally disappears as the vessels mature.2Sauter A. Machura K. Neubauer B. et al.Development of renin expression in the mouse kidney.Kidney Int. 2008; 73: 43-51Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar In the adult kidney, basal renin expression is maintained only in the juxtaglomerular transition zone from afferent arterioles to glomerular capillaries. This characteristic intrarenal distribution pattern of renin-expressing cells during development and in the adult kidney led early on to the concept that renin-producing cells of the kidney may be similar or at least related to pericytes. This assumption was further supported by gene expression profiling of renin cells, which resulted in mRNA profiles compatible with that of pericytes.3Brunskill E.W. Sequeira-Lopez M.L. Pentz E.S. et al.Genes that confer the identity of the renin cell.J Am Soc Nephrol. 2011; 22: 2213-2225Crossref PubMed Scopus (88) Google Scholar Because as yet there exist no unequivocal biochemical markers for pericytes, the question whether renin cells really develop from pericytes or from another mesenchymal cell type resembling pericytes remains open. The paper by Stefanska et al. (2016)4Stefanska A. Kenyon C. Christian H.C. et al.Human kidney pericytes produce renin.Kidney Int. 2016; 90: 1251-1261Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar in this issue provides convincing evidence for renin cells being pericytes. The paper attracts attention for 2 main reasons. First, it combines a broad spectrum of methods ranging from in situ electron microscopical investigations to fluorescence-activated cell sorted cell cultures. Second, it exclusively focuses on the analysis of human embryonic and adult kidneys. For the fetal kidney, Stefanska et al.4Stefanska A. Kenyon C. Christian H.C. et al.Human kidney pericytes produce renin.Kidney Int. 2016; 90: 1251-1261Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar obtained morphological evidence (“peg and socket”) for pericyte-like characteristics of renin-producing cells. They found that human fetal and adult renin cells expressed the pericyte markers CD146 and NG2 and that they surrounded endothelial cells in a fashion typical for pericytes. Furthermore, they found that CD146+CD34−CD45−CD56− renal fetal pericytes sorted by flow cytometry exhibited trilineage mesodermal differentiation potential in vitro including differentiation into renin cells. Finally, the investigators observed that pericytes derived from second trimester human placenta also expressed renin in an inducible fashion that is in accordance with the observation that the placenta is a major site of renin expression during pregnancy. What is the scientific value of the paper by Stefanska et al.4Stefanska A. Kenyon C. Christian H.C. et al.Human kidney pericytes produce renin.Kidney Int. 2016; 90: 1251-1261Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar beyond the experimental confirmation of a long-standing hypothesis? In my opinion, there arise several important aspects from knowing that renin-producing cells are pericytes or pericyte-derived cells. As pericytes are found in all organs, the question arises whether pericytes of extrarenal tissues (such as the placenta) can also produce renin and thus act as starters of local renin-angiotensin systems that many become particularly relevant in states of disease. As pericytes are highly plastic cells sharing similarities with mesenchymal stem cells, they may contribute to cell repopulation after tissue damage (Figure 1). It is of interest in this context that in the adult kidney mesenchymal cells carrying the stem cell marker CD44 can transform into renin cells in states of renin demand.5Yang Y. Gomez J.A. 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: 1047-1054Crossref PubMed Scopus (11) Google Scholar This recruitment process also involves migration of the cells to the juxtaglomerular area, a phenomenon that is also typical for pericytes that are able to migrate. In line with this, renin cells of the adult kidney have been suggested to migrate into the glomerular tuft to repopulate damaged mesangial cells, which are considered a special form of pericytes.6Starke C. Betz H. Hickmann L. et al.Renin lineage cells repopulate the glomerular mesangium after injury.J Am Soc Nephrol. 2015; 26: 48-54Crossref PubMed Scopus (60) Google Scholar Recently, it has also been postulated that renin cells may also transform into podocytes.7Pippin J.W. Kaverina N.V. Eng D.G. et al.Cells of renin lineage are adult pluripotent progenitors in experimental glomerular disease.Am J Physiol Renal Physiol. 2015; 309: F341-F358Crossref PubMed Scopus (45) Google Scholar It has long been well known that renin cells can reversibly transform into vascular smooth muscle-like cells.1Sequeira Lopez M.L. Gomez R.A. Development of the renal arterioles.J Am Soc Nephrol. 2011; 22: 2156-2165Crossref PubMed Scopus (105) Google Scholar Considering this high degree of plasticity of renin cells, we may be encouraged to look for further functions of renin cells based on their striking capability to plasticity. A glimpse for such yet unknown functions of renin cells was provided by the observation that stabilization of the hypoxia-inducible transcription factor 2 transforms renin cells into erythropoietin (EPO)-producing cells, by downregulation of renin expression and upregulation of EPO expression, resembling the typical EPO-producing cells located in the interstitium of the renal cortex and the outer medulla.8Kurt B. Gerl K. Karger C. et al.Chronic hypoxia-inducible transcription factor-2 activation stably transforms juxtaglomerular renin cells into fibroblast-like cells in vivo.J Am Soc Nephrol. 2015; 26: 587-596Crossref PubMed Scopus (27) Google Scholar The normal EPO expressing cells also derive from the FoxD1-positive compartment of the metanephric mesenchyme. Although the nature of these cells has not been identified unequivocally, it is strongly assumed that the EPO expressing cells are capillary pericytes.9Suzuki N. Yamamoto M. Roles of renal erythropoietin-producing (REP) cells in the maintenance of systemic oxygen homeostasis.Pflugers Archiv. 2016; 468: 3-12Crossref PubMed Scopus (44) Google Scholar If so, pericytes of the kidneys would exert fundamental endocrine functions by the secretion of EPO and of renin into the circulation (Figure 1). Both types of pericytes would act in concert to determine blood volume and the number of red blood cells and finally oxygen transport to the tissues. This aspect is emphasized along with the fact that periyctes are widely distributed among all organs, but that so far only renal pericytes appear to exert this combination of specific and important systemic endocrine functions. At first glance, it would appear as though renal pericytes around small vessels (capillaries) produce EPO, whereas those surrounding somewhat bigger vessels (afferent arterioles) produce renin. In other words, preglomerular pericytes seem to have the capability to produce renin, whereas postglomerular pericytes seem to be capable of producing erythropoietin. The 2 renal pericyte subtypes also appear to have different physiologically relevant sensor functions. It is thought that the pericytic renin cells sense the blood pressure (renal barosensor) and the pericytic erythropoietin-producing cells sense the oxygen tension and oxygen content of the blood (renal oxygen sensor). To find out whether this endocrine specialization of renal pericytes results from specific local inducers or suppressors during kidney development should be a fascinating task for future basic research. Furthermore, capillary pericytes can transform into myofibroblasts and thus they significantly contribute to renal fibrosis. Whether the pericytic renin-secreting cells do also transform into myofibroblasts in diseased kidneys is yet unknown and should be investigated. The author declared no competing interests. Human kidney pericytes produce reninKidney InternationalVol. 90Issue 6PreviewPericytes, perivascular cells embedded in the microvascular wall, are crucial for vascular homeostasis. These cells also play diverse roles in tissue development and regeneration as multi-lineage progenitors, immunomodulatory cells and as sources of trophic factors. Here, we establish that pericytes are renin producing cells in the human kidney. Renin was localized by immunohistochemistry in CD146 and NG2 expressing pericytes, surrounding juxtaglomerular and afferent arterioles. Similar to pericytes from other organs, CD146+CD34–CD45–CD56– renal fetal pericytes, sorted by flow cytometry, exhibited tri-lineage mesodermal differentiation potential in vitro. Full-Text PDF Open Access