BRIEF REVIEW www.jasn.org Development of the Renal Arterioles Maria Luisa S. Sequeira Lopez and R. Ariel Gomez Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia ABSTRACT The kidney is a highly vascularized organ that normally receives a fifth of the first arterioles are seen around 15 to 16 cardiac output. The unique spatial arrangement of the kidney vasculature with each days of gestation. By 18 to 19 days of ges- nephron is crucial for the regulation of renal blood flow, GFR, urine concentration, tation, there is a basic blueprint of arte- and other specialized kidney functions. Thus, the proper and timely assembly of rial and arteriolar development.15 This is kidney vessels with their respective nephrons is a crucial morphogenetic event followed in the ensuing days by a burst of leading to the formation of a functioning kidney necessary for independent extra- branching and elongation of new arteri- uterine life. Mechanisms that govern the development of the kidney vasculature oles that repeat the basic pattern for are poorly understood. In this review, we discuss the anatomical development, about a week after birth, resulting in a embryological origin, lineage relationships, and key regulators of the kidney arte- remarkable increase in the complexity rioles and postglomerular circulation. Because renal disease is associated with and surface area of the vasculature. These deterioration of the kidney microvasculature and/or the reenactment of embryonic orchestrated series of events require that pathways, understanding the morphogenetic events and processes that maintain progenitor cells differentiate, acquire po- the renal vasculature may open new avenues for the preservation of renal structure sitional information, assemble in the and function and prevent the progression of renal disease. right location within the vessel, and seg- regate those cells that participate in J Am Soc Nephrol 22: 2156–2165, 2011. doi: 10.1681/ASN.2011080818 branching. When this process fails, the consequences are devastating as exem- plified by the serious developmental de- The mechanisms that govern the devel- into the renal mesenchyme. As the ureter fects described below, which occur (par- opment of the kidney vasculature are branches, the mesenchymal cells con- ticularly in the newborn period when poorly understood. In this brief review, dense around each ureteric tip. The con- branching is at its peak) in animals and we discuss the anatomical development, densate develops into a vesicle, followed humans with ablation of renin cell pre- embryological origin, lineage relation- by a comma-shaped body that subse- cursors, mutations of the renin-angio- ships, and key regulators of the kidney quently develops into an S-shaped body. tensin system, and lack of microRNAs in arterioles and postglomerular circula- Simultaneously, the glomerular cells dif- the renal vasculature, resulting in early tion. For other important regulatory ferentiate until they acquire their adult arterial and arteriolar abnormalities that molecules and mechanisms already features. In humans, nephrogenesis is are followed by deterioration of kidney demonstrated for nonrenal vessels, as complete by 34 to 35 weeks of gestation. structure and function.15–23 In spite of its well as for the development of the glo- In mice and rats, however, nephrogen- importance, very little is known about merular capillaries, the reader is referred esis continues after birth for about 3 to 7 the fate of the vascular precursors and to some excellent reviews.1–14 days, respectively. the mechanisms that lead them to differ- In vivo, vascularization of the kidney entiate and assemble into the kidney ar- is synchronized with epithelial nephro- Anatomical Development of the terioles. genesis. Nephrogenesis of the definitive Renal Arterial Tree kidney results from the reciprocal induc- Using microdissection techniques com- Published online ahead of print. Publication date tive interaction between the primitive ure- bined with histologic assessment, we available at www.jasn.org. teric bud and the metanephric mesen- studied the anatomical development of Correspondence: Dr. Maria Luisa S. Sequeira Lo- chyme (Figure 1). The ureteric bud the renal arterial tree in mice and rats pez, University of Virginia School of Medicine, 409 Lane Road, MR4 Building, Room 2001, Charlottes- induces the mesenchyme to form tubular throughout embryonic and postnatal ville, VA 22908. Phone: 434-924-5065; Fax: 434- and glomerular epithelia. In turn, the life, including adulthood (unpublished 982-4328; E-mail: [email protected] surrounding mesenchyme induces the observations and Figure 2). Those stud- Copyright © 2011 by the American Society of ureter to continue to grow and branch ies reveal that in the mouse kidney, the Nephrology 2156 ISSN : 1046-6673/2212-2156 J Am Soc Nephrol 22: 2156–2165, 2011 www.jasn.org BRIEF REVIEW Collecting Glomerulus Proximal duct tube Condensate Distal tube Metanephric mesenchyme Proximal Vascular tube progenitors Distal tube Ureteric bud Vesicle Comma-shaped S-shaped Figure 1. Nephrogenesis results from the interaction between the ureteric bud and the metanephric mesenchyme. Schematic of nephrogenesis. See text for details (adapted from reference 62). a Foxd1ϩ cell from which all other arte- rial and perivascular/adventitial cells originate (Figure 3). Hemogenic Progenitors. It is now accepted that hematopoietic stem cells (HSCs) and ECs originate dur- ing embryogenesis from a common pro- genitor, the hemangioblast.26,27 These cells consist of a subpopulation of the Figure 2. Increased complexity of the renal arterial tree during development. Microdis- primitive streak mesoderm that migrates section of the entire preglomerular arteriolar tree at different developmental time points to the yolk sac where they establish the is shown at the same magnification. primitive hematopoietic system. Primi- tive erythroid progenitors expand within Vascular Progenitors and Arteriolar very early, well before vessels can be dis- the yolk sac and at embryonic day (E)8.5 Development cerned. It is also clear that those precur- enter the newly developing circulation As mentioned above, for nephrons to sors differentiate into all of the cell types and continue to mature. As soon as the function properly, each glomerulus necessary for the development of the kid- liver starts to form, they home to it, must establish its own circulation. ney arterioles, including endothelial cells where they complete their maturation Blood enters the glomerulus through (ECs), smooth muscle cells (SMCs), and and enucleate.28 On the other hand, de- an afferent arteriole that is continued renin cells.24,25 Furthermore, cross- finitive hematopoiesis is established by glomerular capillaries where filtra- transplantation studies of those embry- within the embryo proper in the para- tion occurs and leaves the glomerulus onic prevascular kidneys under the kid- aortic splachnopleural region by regional through an efferent arteriole (Figure 3). ney capsule of a host mouse allowed us hemangioblasts or hemogenic endothe- The establishment of these nephrovascu- and others to demonstrate that precursor lium, which supports the development of lar units is a remarkable morphogenetic cells have the capacity to differentiate, HSCs. Primitive hematopoiesis gener- event requiring spatial and temporal co- acquire the right positional information, ates mainly nucleated primitive erythro- ordination of the cells destined to form and fully assemble to form the kidney ar- cytes, whereas definitive hematopoiesis these structures. Despite the critical rele- terioles.24 The origin, lineage relation- generates all hematopoietic lineages, in- vance of this process, the actual events ships, and morphogenesis of the kidney cluding nucleated and enucleated de- and molecules that control the forma- vasculature are also not well understood. finitive erythrocytes and HSCs with a tion of the kidney arterioles are unclear. Within the stromal compartment, we long-term repopulating activity. Using At the time of the first division of the ure- identified two putative and distinct early multiple techniques including Tie2.Cre; teric bud, within the metanephric mes- progenitor cells that give rise to all cells of R26R lineage tracing, electron micros- enchyme (ϳE12 mouse, E14 rat), the the kidney arterioles and their perivascu- copy, laser capture microdissection, or- embryonic kidneys do not have arterio- lar compartment. Those progenitors are gan culture, and cross-transplantation lar vessels. Whereas renal and extrarenal a precursor of hemogenic endothel- experiments, we showed there is a lineage origins have been suggested for the renal ium—provisionally called renal heman- relationship between ECs and HSCs dur- vasculature, it is clear that progenitors gioblasts—capable of giving rise to ery- ing embryonic development and the are present in the metanephric kidney throid and ECs of the renal arteriole and presence of HSCs budding from the en- J Am Soc Nephrol 22: 2156–2165, 2011 Development of the Renal Arterioles 2157 BRIEF REVIEW www.jasn.org beled mice with traceable reporters al- lowed further experiments in mice. Hemangioblast Foxd1+ cell When embryonic kidneys are trans- Flk-1+ + planted into the anterior chamber of the Flk-1 Tie2+ + Tie2 Kit+ + eye or under the kidney capsule of adult Kit VE-cadherin+ + VE-cadherin Tie2+ hosts, the embryonic kidneys develop a + SMA proper vasculature with all of the vascu- Endothelial