juxtaglomerular (JG) cells, which are renin-secreting, specialized smooth muscle cells (also known as granular myoepithelial cells), are located within the wall of the afferent arteriole near the point where it enters the glomerulus (12). JG cells are therefore intimate members of the juxtaglomerular apparatus (JGA), which is also comprised of the macula densa epithelial plaque at the terminus of the thick ascending limb of Henle's loop, extraglomerular mesangial cells, and the vascular endothelium and smooth muscle cells associated with the glomerular vascular pole (12). Among all of these cell types, JG cells are uniquely characterized by their numerous renin-containing granules (5, 12). Renin release from JG granules is the key first step in the enzymatic activation of the renin-angiotensin system (RAS), which is chiefly responsible for regulating systemic blood pressure, glomerular filtration and nephron fluid flow rates, and electrolyte balance. The presence of myofilaments, peroxisomes, and few mitochondria are also hallmarks of JG cells (12).
RAS and, by extension, JG cells have for some time been suspected of mediating crucial events important for vascular development in the kidney. In fully mature kidneys, renin-expressing cells are found exclusively in the JGA (1, 11), whereas during development, renin cells are also found in larger vessels in addition to the afferent arteriole of developing glomeruli (3, 7, 10). Interstitial cells of prevascular embryonic day 14 (E14) rat kidneys contain renin-positive cells (9), and transplantation of E12 mouse kidneys bearing lineage markers shows that cells expressing renin derive from the metanephric blastema (6). Moreover, renin is expressed before smooth muscle markers, suggesting that some vascular smooth muscle cells may also be derivatives from these embryonic, renin-expressing precursors (6). To further implicate renin cells and RAS in renal vascular development, genetic alterations in individual RAS components lead to severe vascular abnormalities (reviewed in Ref. 2). Deletion of angiotensinogen and angiotensin receptors AT1A/AT1B results in thickened blood vessel walls with smaller or obstructed lumens (13). Mice lacking the angiotensin-converting enzyme (ACE) show severe endothelial hypercellularity in arterioles and extremely thickened blood vessel walls (4). Microdissection of the arteriolar tree from ACE null mice shows a decrease in number of afferent arterioles (4). Collectively, these data strongly suggest that renin-expressing cells and/or a completely intact RAS are required for proper kidney vascular development.
Until now, there has been no simple way of dissecting this issue further to determine whether renal vascular formation is reliant on renin itself or whether the cells that secrete renin (JG cells) are somehow involved independent of renin. An elegant study appearing in this issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology by Pentz and coworkers (8), suggests quite surprisingly that renin-secreting cells (and therefore probably RAS) are not absolutely required for proper vascular development in the kidney. In this study, a mouse was created through homologous recombination that is almost entirely devoid of kidney renin cells. This was achieved by expressing diphtheria toxin A chain (DTA) under control of the Ren1d renin promoter in a strain that expresses two renin genes (Ren1d and Ren2). The toxin essentially eliminates all renin cells from kidneys in these mice, although Ren2-driven renin expression in the submandibular gland persists (8). The severe decrement of renal JG cells therefore indicates that both Ren1d and Ren2 genes are probably expressed by the same cells in the kidney. Importantly, the DTA/DTA mice are viable and have apparently normal renal vascular architecture. However, and despite the formation of normal renal vasculature, they nevertheless display prominent defects in kidney morphology and ultimately suffer renal failure. Kidneys of DTA/DTA homozygotes are small and weigh significantly less than those of wild-type littermates. The cortex of mutant mice is much thinner and ∼25% of glomeruli are hyperplastic or atrophic and most tubules have expanded lumens and are atrophic. In addition, mutant kidneys contain a large population of undifferentiated cells (residual, uninduced metanephric mesenchyme?), providing further evidence that kidney development is obscured and/or stunted in these mice. The renin concentration in knockouts is reduced to 10-20% of normal levels, and females have extremely low blood pressure. In males, blood pressure is variable, but trends lower than normal. Blood urea nitrogen and potassium levels are significantly elevated in mature DTA/DTA animals, providing functional evidence that these mice are undergoing renal failure. These kidney defects, compared with other RAS mutants, clearly demonstrate that renin cells themselves have an indispensable role for acquisition or maintenance of normal kidney structure and function. As the authors speculate, future studies with these mice may prove helpful in understanding the role of JG cells in homeostatic responses to a variety of environmental stimuli (such as dehydration or kidney injury).
A very surprising and significant finding in this study is that the renal vasculature develops apparently normally in virtually the complete absence of renin-expressing JG cells. This is in stark contrast to the severe vascular defects found in RAS mutant mice, which display stunted growth of renal vascular trees and thickened vascular walls (2, 4, 13). Insofar as RAS gene knockout studies can identify a function for RAS components in vascular development, the current study shows that these vascular defects may not be a consequence merely of RAS ablation, but instead may be a result of the physical presence of renin cells. Whereas RAS mutants contain increased numbers of renin cells and recruitment of these cells to vessels undergoing hypertrophy, the DTA/DTA mice reported here lack both renin expressing cells and the ability to mobilize renin cells to vessels, and these vessels do not hypertrophy. The authors conclude that the vascular abnormalities seen in RAS knockouts may therefore be independent of RAS and caused instead by other factors derived from the renin-expressing JG cells themselves. This signal has yet to be identified, but could include other secreted factors from renin-positive cells or could be a result of direct cell/cell contact between renin cells and vascular smooth muscle and/or endothelial cells of hypertrophic vessels. In sum, this fascinating paper that selectively deletes a single cellular component of the JGA clearly points to previously unrecognized functions of JG cells that extend beyond their well known role in secreting renin. Future studies with these novel knockouts may provide a much fuller understanding of JG cell biology.
- Copyright © 2004 the American Physiological Society