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• W2022105925 abstract "Role of angiotensin in kidney and urinary tract congenital anomalies in the mouse and the human. The role of angiotensin in fluid and electrolyte and blood pressure homeostasis is well known. Recent developments indicate that angiotensin has a profound role not only in the developing urinary tract but also in the response of the urinary tract to specific noxious stimuli. Furthermore, the role of angiotensin II and its receptor has been understood quite poorly with respect to the developing renal unit. Knockout mice for the ATR2 gene show a significant incidence of congenital urinary tract anomalies. The congenital anomalies of the kidney and urinary tract (CAKUT) seen in these mice are very similar to the anomalies observed in humans. This has been supported further by the finding of an abnormality in the genetic sequence in patients with CAKUT. This article reviews experimental laboratory data as well as the potential implications for humans. Role of angiotensin in kidney and urinary tract congenital anomalies in the mouse and the human. The role of angiotensin in fluid and electrolyte and blood pressure homeostasis is well known. Recent developments indicate that angiotensin has a profound role not only in the developing urinary tract but also in the response of the urinary tract to specific noxious stimuli. Furthermore, the role of angiotensin II and its receptor has been understood quite poorly with respect to the developing renal unit. Knockout mice for the ATR2 gene show a significant incidence of congenital urinary tract anomalies. The congenital anomalies of the kidney and urinary tract (CAKUT) seen in these mice are very similar to the anomalies observed in humans. This has been supported further by the finding of an abnormality in the genetic sequence in patients with CAKUT. This article reviews experimental laboratory data as well as the potential implications for humans. Angiotensin type 1 receptor gene Angiotensin type 2 receptor gene angiotensin Ang type 1 embryonic congenital anomalies of the kidney and urinary tract multicystic dysplastic kidney ureteropelvic junction Angiotensin (Ang) is best known for its role in the regulation of blood pressure. Ang achieves its homeostatic function highly efficiently, that is, by concurrently utilizing several biological measures, such as, regulation of aldosterone synthesis, salt appetite, and peripheral vascular resistance. As in many other homeostatic mechanisms, the generation of Ang, in turn, is regulated in a remarkably precise manner. Thus, when renal perfusion pressure falls, such as, as a result of dehydration or mechanical hindrance to renal arterial blood flow, the release of renin, and hence Ang, surges Figure 1. Ang continues to increase, raising systemic blood pressure so that renal perfusion pressure returns to a near baseline level Figure 1. Thanks to the pioneering work of Dr. Thurau, his associates, and other investigators, we now know that the macula densa and the juxtaglomerular apparatus are the key players in this feedback regulation of renin-angiotensin release1.Dahlheim H. Granger P. Thurau K. A sensitive method for determination of renin activity in the single juxtaglomerular apparatus of the rat kidney.Pflügers Arch. 1970; 321: 303-315Crossref PubMed Scopus (21) Google Scholar,3.Schnermann J. Briggs J. Role of the renin-angiotensin system in tubuloglomerular feedback.Fed Proc. 1986; 45: 1426-1430PubMed Google Scholar. Overall, the kidney is designed to preserve its own hydrodynamic environment, and Ang is a biological tool to perform this function. Renin-angiotensin release also surges when urine outflow is mechanically hindered Figure 14.Pimentel Jr, J.L. Martinez-Maldonado M. Wilcox J.N. Wang S. Luo C. Regulation of renin-angiotensin system in unilateral ureteral obstruction.Kidney Int. 1993; 44: 390-400Abstract Full Text PDF PubMed Scopus (79) Google Scholar. This phenomenon of ureteral pressure-sensitive activation of renin-angiotensin has been heretofore viewed as an error of nature and often even as harmful to the kidney5.Ishidoya S. Morrissey J. Mc Cracken R. Reys A. Klahr S. Angiotensin II receptor antagonist ameliorates renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction.Kidney Int. 1995; 47: 1285-1294Abstract Full Text PDF PubMed Scopus (322) Google Scholar. The challenge to this traditional view came when we examined several strains of mutant mice that are completely devoid of either Ang type 1 (AT1) receptor gene (Agtr1) or Ang type 2 (AT2) receptor gene (Agtr2) as a result of genetic manipulation of these genes6.Nishimura H, Yerkes E, Hernanz-Schulman M, Fogo A, Kon V, Hogan BLM, Phillips JA III, Brock JW III, Inagami T, Ichikawa I: Null mutation of the murine angiotensin type 2 receptor gene produces a spectrum of phenotypes resembling human congenital anomalies of the kidney and urinary tract (CAKUT). J Am Soc Nephrol (in press)Google Scholar,7.Tsuchida S. Matsusaka T. Chen X. Okubo S. Niimura F. Nishimura H. Fogo A. Inagami T. Ichikawa I. Murine double nullizygotes of the angiotensin type 1A and 1B receptor genes have the same abnormal phenotypes as angiotensinogen nullizygotes and more.J Am Soc Nephrol. 1997Google Scholar. As discussed in more detail later here, these strains of mice display varying degrees of urinary tract obstruction, either structural or functional in nature. Some obstructions develop during early kidney ontogenesis in utero and others during late ontogenesis ex utero. One may recall that, throughout normal ontogenesis, the kidney is constantly at risk for obstruction of urine outflow. Thus, in utero [∼embryonic (E) day 14 in mice; ∼day E40 in humans], the ureter is transiently obliterated8.Alcaraz A. Vinaixa F. Tejedo-Mateu A. Fores M.M. Gotzens V. Mestres C.A. Oliveira J. Carretero P. Obstruction and recanalization of the ureter during embryonic development.J Urol. 1991; 145: 410-416PubMed Google Scholar. This transient obliteration is believed to protect the kidney from the high pressure from the cloaca when urine is not yet formed. During this period, dense layers of undifferentiated mesenchymal cells surround the ureter. Subsequent expansive growth that the ureter must achieve, therefore, occurs in concert with the timely disappearance of the surrounding mesenchymal cells. The study in mouse embryos with Agtr2 null mutation6.Nishimura H, Yerkes E, Hernanz-Schulman M, Fogo A, Kon V, Hogan BLM, Phillips JA III, Brock JW III, Inagami T, Ichikawa I: Null mutation of the murine angiotensin type 2 receptor gene produces a spectrum of phenotypes resembling human congenital anomalies of the kidney and urinary tract (CAKUT). J Am Soc Nephrol (in press)Google Scholar indicated that Ang, through the AT2 receptor, promotes disappearance of these mesenchymal cells and that inactivation of this receptor results in congenital obstructive nephropathy. Once animals are born, the kidney assumes primary importance for preservation of body fluid homeostasis, and urinary output increases dramatically. The large volume of urine predisposes the kidney to obstructive nephropathy due to the high resistance offered to the urine by the downstream ureter. Normally, a special device develops within the urinary tract in a timely fashion that enables the kidney to collect a bulk of urine and then to expel it downward periodically without imposing positive pressure on the renal parenchyma. This special device is the renal pelvis, which comprises smooth muscle cells with a pacemaker function9.Dixon J.S. Gosling J.A. The musculature of the human renal calices, pelvis and upper ureter.J Anat. 1982; 135: 129-137PubMed Google Scholar. The pacemaker cells initiate the chain reaction of peristalsis downward. Remarkably, the muscle cells of the pelvis are distributed not only outside the perimeter of the renal parenchyma, but also extensively inside, so that the co-ordinated contraction of the pelvis prevents transmission of positive pressure to the renal parenchyma by transiently shutting off communication between the calyx and the pelvis. As described later here, in a recent series of studies on Agtr1 null mutant mice7.Tsuchida S. Matsusaka T. Chen X. Okubo S. Niimura F. Nishimura H. Fogo A. Inagami T. Ichikawa I. Murine double nullizygotes of the angiotensin type 1A and 1B receptor genes have the same abnormal phenotypes as angiotensinogen nullizygotes and more.J Am Soc Nephrol. 1997Google Scholar, Ang, through the AT1 receptor, promotes development of the pacemaker cells within the pelvis shortly after birth so that inactivation of this receptor leads to absence of development of the pelvis, hence to obstructive nephropathy. Collectively, the studies on Agtr1 or Agtr2 null mutant mice indicate that the animals that lack intact Ang receptor systems suffer from urinary tract obstruction. Given that urinary tract obstruction per se is a potent stimulus for Ang generation, the observed function of Ang to allow the kidney to escape from obstructive nephropathy is functionally significant and biologically important. This mechanism has all of the necessary components of an effective feedback mechanism; that is, the mechanism has a sensor to a stimulatory signal (that is, ureteral pressure), and the activated mediator (that is, Ang) is geared toward dampening the signal toward baseline level. Yet to be determined is whether this feedback system, seemingly important in avoiding obstructive nephropathy in growing animals, also functions in mature animals. The embryonic development of the kidney and urinary tract takes place in concert with the disappearance of undifferentiated mesenchymal cells, which densely surround the Wolffian duct initially, then, the ureter and nephronogenic centers within the metanephros10.Kakuchi J. Ichiki T. Kiyama S. Hogan B.L.M. Fogo A. Inagani T. Ichikawa I. Developmental expression of renal angiotensin II receptor genes in the mouse.Kidney Int. 1995; 47: 140-147Abstract Full Text PDF PubMed Scopus (155) Google Scholar. AT2 receptor transcriptional activity is transiently up-regulated in utero in close association with the disappearance of these mesenchymal cells. Mice carrying a targeted null mutation of Agtr2 sometimes display congenital anomalies of the kidney and urinary tract (CAKUT)6.Nishimura H, Yerkes E, Hernanz-Schulman M, Fogo A, Kon V, Hogan BLM, Phillips JA III, Brock JW III, Inagami T, Ichikawa I: Null mutation of the murine angiotensin type 2 receptor gene produces a spectrum of phenotypes resembling human congenital anomalies of the kidney and urinary tract (CAKUT). J Am Soc Nephrol (in press)Google Scholar. CAKUT are male-preponderant and predominantly unilateral and include the following defects, either alone or in combination: hypoplastic kidney, multicystic dysplastic kidney (MCDK), ureteropelvic junction (UPJ) stenosis/atresia, and megaureter. Mild reflux of urine from the bladder to the ureter afflicts more null mutants without gross anatomical anomalies. In addition to all of the previously mentioned features, other characteristic features, including histological patterns, the onset of anomalies in utero, and absence of other somatic defects, also closely mimic those of human CAKUT. To determine if variants of the Agtr2 gene underlie the manifestation of CAKUT in humans, we analyzed the AT2 genes from a cohort of United States Caucasians with UPJ obstruction with or without or MCDK and controls11.Yerkes E, Nishimura H, Hunley TE, Kon V, Phillips JA III, Brock JW III Ichikawa I: Association between the angiotensin type 2 receptor genotype and congenital urinary tract anomalies in two independent cohorts. J Am Soc Nephrol (in press)Google Scholar. Using genomic DNA from five patients and two controls as templates, polymerase chain reaction amplicons containing exons 1 to 3 and introns 1 and 2 of the Agtr2 gene were obtained. These amplicons were then screened for sequence alterations by dideoxy fingerprinting followed by DNA sequencing. We identified only one polymorphic locus in the ∼2.5-kb length examined, which is an A to G transition within intron 1. This transition occurred in 74% of the 23 affected males, but only 19% of the 16 controls (χ2 = 11.5, P < 0.001). Thus, our studies identified a nucleotide transition in the human AT2 gene that is associated with UPJ obstruction and/or MCDK. These findings suggest that the AT2 gene variance in the polymorphic locus identified in the study or a nearby mutation may also contribute to other forms of CAKUT in humans. To explore the mechanism through which defective AT2 receptor may cause CAKUT, we studied the effect of Ang (10-6m) on the ureter dissected from E14.5 mouse embryos and cultured in vitro12.Miyazaki Y. Nishimura H. Harris R.C. Mc Kanna J. Inagami T. Ichikawa I. Angiotensin regulates embryonic development of the ureter via type 1 (AT1) and type 2 (AT2) receptors.J Am Soc Nephrol. 1997Google Scholar. Under the culture conditions that we established, the ureter grows and differentiates and is characterized by a simple epithelial tubelike structure surrounded by dense undifferentiated mesenchymal cell layers that express AT2 mRNAs. Ureters were then nick labeled to quantify the activity of apoptosis. Studies were then conducted on ureters from both wild-type and Agtr2 null mutant embryos. Results showed that treatment with Ang II, but not vehicle alone, increases nick-positive cells among undifferentiated mesenchymal cells in the wild-type ureter. In contrast, Ang II treatment did not increase nick positivity in ureters from Agtr2 null mutant embryos. Additionally, microscopic studies on Agtr2 null mutant embryos further identified delayed apoptosis of undifferentiated mesenchymal cells in utero as an intermediary phenotype preceding CAKUT in the mutant. Collectively, these results indicate first that embryonic activation of the AT2 receptor has a significant role in the normal growth and development of the kidney and ureter. Second, the diverse anatomical patterns of CAKUT share a common ontogenic mechanism of delayed apoptosis of UMCs, which hinders key events of kidney and urinary tract development from the first ureteral budding to their subsequent expansive physical growth. Rodents are the unique species carrying duplicated AT1 receptor genes, Agtr1a and Agtr1b. After separately generating Agtr1a and Agtr1b null mutant mice by gene targeting, we produced double mutant mice homozygous for both Agtr1a and Agtr1b null mutation (Agtr1-/-) by mating the single gene mutants7.Tsuchida S. Matsusaka T. Chen X. Okubo S. Niimura F. Nishimura H. Fogo A. Inagami T. Ichikawa I. Murine double nullizygotes of the angiotensin type 1A and 1B receptor genes have the same abnormal phenotypes as angiotensinogen nullizygotes and more.J Am Soc Nephrol. 1997Google Scholar. Agtr1-/- mice are characterized by normal in utero survival rate but decreased ex utero survival. Although the kidneys are macroscopically and microscopically essentially indistinguishable from those of wild-type mice at birth, they develop, by three weeks of age, pronounced lesions in the renal cortex. In addition, the papillae of homozygous mutant kidneys are reduced in size, and the calices are expanded. Although these lesions are progressive in nature, no discernible pelvic structure develops in null mutant mice, contrasting to the rapid development of the pelvis seen shortly after birth in wild-type mice. Thus, the AT1 receptor is essential for newborn mice to develop pelvic structure, without which a typical hydronephrotic pattern develops in the kidney. Using the ureter dissected from E14.5 mouse embryos, we therefore studied the role of the AT1 receptor for the ureteral smooth muscle cell development12.Miyazaki Y. Nishimura H. Harris R.C. Mc Kanna J. Inagami T. Ichikawa I. Angiotensin regulates embryonic development of the ureter via type 1 (AT1) and type 2 (AT2) receptors.J Am Soc Nephrol. 1997Google Scholar. E14.5 wild-type and Agtr1 null mutant embryonic ureters were dissected and incubated. Two ureters from each embryo were treated with either vehicle alone or Ang II (10-6m) for 24 hours. The ureters were stained for α actin to assess differentiation of the mesenchyme into smooth muscle. Treatment with Ang II, but not vehicle alone, leads to the appearance of distinctive smooth muscle cell layers around the epithelium in the wild-type ureter but not those from Agtr1 null mutants. We conclude that Ang II affects the embryonic ureter and promotes differentiation into the smooth muscle via AT1 and that inactivation of these receptors in null mutants may lead to functional obstruction of the urinary tract system." @default.
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• W2022105925 title "Role of angiotensin in the congenital anomalies of the kidney and urinary tract in the mouse and the human" @default.
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