Renin in human fetal lung ??? a biochemical and immunohistochemical study

Taylor, G. M.; Cook, H. Terence; Hanson, Corrine; Peart, W. S.; Zondek, Theodor; Zondek, Lilly H.

doi:10.1097/00004872-198810000-00012

Cited by 14 publications

(9 citation statements)

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“…hREN gene expression was also detected in the lung of all other hREN TG lines ( Table 2) and has been reported in human fetal lung. 33 However, in each case, the cellular localization differed: in the present study, we found hREN immunoreactivity primarily in bronchiolar epithelial cells; in 13-kb TG mice, hREN mRNA was localized to type II epithelial cells 34 ; and in human fetal lung, renin was localized to endothelial cells. 33 Renin has also been detected in human pulmonary tumors [35][36][37] and in a human pulmonary carcinoma cell line (Calu-6).…”

Section: Discussioncontrasting

confidence: 62%

“…33 However, in each case, the cellular localization differed: in the present study, we found hREN immunoreactivity primarily in bronchiolar epithelial cells; in 13-kb TG mice, hREN mRNA was localized to type II epithelial cells 34 ; and in human fetal lung, renin was localized to endothelial cells. 33 Renin has also been detected in human pulmonary tumors [35][36][37] and in a human pulmonary carcinoma cell line (Calu-6). 34 Because lung neoplasms ectopically express many other polypeptide hormones, 38 lung tissue may more readily express a variety of genes, and renin gene expression may be readily activated if all the necessary regulatory mechanisms are absent or compromised.…”

Section: Discussioncontrasting

confidence: 62%

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Kidney Is the Only Source of Human Plasma Renin in 45-kb Human Renin Transgenic Mice

Yan

Chen

Pitarresi

et al. 1998

Circulation Research

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Prorenin is expressed in certain extrarenal tissues, but normally only the kidneys process prorenin to renin and secrete renin into the circulation. Although transgenic animal lines containing the human renin (hREN) structural gene with either 0.9-kb or 3-kb 5'-flanking DNA express the transgene appropriately in renal juxtaglomerular cells and secrete hREN into the circulation, the source of the circulating renin is not known. In the present study, we observed that 13-kb hREN transgenic mice that contain the structural gene and 0.9-kb 5'-flanking DNA express hREN mRNA in many unusual tissues. We also observed that circulating hREN levels in 13-kb hREN mice increased after bilateral nephrectomy. These results suggested that the hREN gene is expressed at inappropriate locations where prorenin might be processed to renin. To determine if more distal sequences flanking the hREN gene might contribute to cell and tissue specificity, we used a 45-kb hREN genomic fragment that contained the structural gene and about 25-kb 5'- and 8-kb 3'-flanking DNA sequences to generate 3 separate transgenic lines that contained the intact transgene sequences. Ribonuclease protection assays revealed a much narrower tissue distribution of hREN expression than in the 13-kb hREN transgenic mice. In each 45-kb hREN line, hREN mRNA was present only in the kidney, adrenal, lung, eye, ovary, and brain. Moreover, 24 hours after nephrectomy, human plasma renin fell to very low levels, indistinguishable from those of nontransgenic littermates, indicating that their circulating hREN is of renal origin. These studies suggest that sequences flanking the structural gene, missing from previous hREN transgenic lines, suppress renin gene expression at inappropriate extrarenal sites where cellular proteases, to which prorenin is not normally exposed, could convert prorenin to renin, resulting in abnormal secretion of renin into the plasma.

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Section: Discussioncontrasting

confidence: 62%

Section: Discussioncontrasting

confidence: 62%

Kidney Is the Only Source of Human Plasma Renin in 45-kb Human Renin Transgenic Mice

Yan

Chen

Pitarresi

et al. 1998

Circulation Research

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“…Given the notion that, in many aspects, the renal function and structure of neonatal rodents resemble those of human embryos at the third trimester, the possibility is raised that the renal anomaly of ACE inhibitor fetopathy is, in part, related to the defective development of urinary peristalsis. Incidentally, in humans, a drastic increase in urine flow rate occurs during the third trimester (34), and the renal pelvis develops during this period as well (35), along with an upregulation of renal angiotensin (36).…”

Section: Discussionmentioning

confidence: 99%

“…The first relates to the onset of extrauterine life as the timing of angiotensin upregulation. The renin-angiotensin system is transiently upregulated during the perinatal period (36,37), the significance of which has long been debated (38), as pharmacological inhibition has little effect as far as acute hemodynamic changes are concerned. In view of the dramatic increase in urine flow during the perinatal period, the angiotensin upregulation appears very timely so that the pelvis can be induced promptly to accommodate this physiological stress unique to mammals.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin induces the urinary peristaltic machinery during the perinatal period.

Miyazaki¹,

Tsuchida²,

Nishimura³

et al. 1998

J. Clin. Invest.

141

117

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The embryonic development of mammalian kidneys is completed during the perinatal period with a dramatic increase in urine production, as the burden of eliminating nitrogenous metabolic waste shifts from the placenta to the kidney. This urine is normally removed by peristaltic contraction of the renal pelvis, a smooth muscle structure unique to placental mammals. Mutant mice completely lacking angiotensin type 1 receptor genes do not develop a renal pelvis, resulting in the buildup of urine and progressive kidney damage. In mutants the ureteral smooth muscle layer is hypoplastic and lacks peristaltic movements. We show that angiotensin can induce the ureteral smooth muscles in organ cultures of wild-type, but not mutant, ureteral tissues and that, in wild-type mice, expression of both renal angiotensin and the receptor are transiently upregulated at the renal outlet at birth. These results reveal a new role for angiotensin in the unique cellular adaptations of the mammalian kidney to the physiological stresses of postnatal life. ( J.

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“…Reports of renin synthesis in the normal human fetal lung, as well as in vascular and nonvascular cells in the diseased lungs of adults (44,67,68,70), suggest an important role for renin in the normal and diseased lung. Thus renin transgene overexpression in this rodent model may reflect one of the pathogenic factors involved in PH in humans.…”

Section: Methodological Considerationsmentioning

confidence: 99%

Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat

DeMarco

Habibi

Whaley‐Connell

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Dellsperger KC. Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat. Am J Physiol Heart Circ Physiol 294: H2659-H2668, 2008. First published April 18, 2008 doi:10.1152/ajpheart.00953.2007.-The transgenic (mRen2)27 (Ren2) rat overexpresses mouse renin in extrarenal tissues, causing increased local synthesis of ANG II, oxidative stress, and hypertension. However, little is known about the role of oxidative stress induced by the tissue renin-angiotensin system (RAS) as a contributing factor in pulmonary hypertension (PH). Using male Ren2 rats, we test the hypothesis that lung tissue RAS overexpression and resultant oxidative stress contribute to PH and pulmonary vascular remodeling. Mean arterial pressure (MAP), right ventricular systolic pressure (RVSP), and wall thickness of small pulmonary arteries (PA), as well as intrapulmonary NADPH oxidase activity and subunit protein expression and reactive oxygen species (ROS), were compared in age-matched Ren2 and Sprague-Dawley (SD) rats pretreated with the SOD/catalase mimetic tempol for 21 days. In placebo-treated Ren2 rats, MAP and RVSP, as well as intrapulmonary NADPH oxidase activity and subunits (Nox2, p22 phox , and Rac-1) and ROS, were elevated compared with placebo-treated SD rats (P Ͻ 0.05). Tempol decreased RVSP (P Ͻ 0.05), but not MAP, in Ren2 rats. Tempol also reduced intrapulmonary NADPH oxidase activity, Nox2, p22 phox , and Rac-1 protein expression, and ROS in Ren2 rats (P Ͻ 0.05). Compared with SD rats, the cross-sectional surface area of small PA was 38% greater (P Ͻ 0.001) and luminal surface area was 54% less (P Ͻ 0.001) in Ren2 rats. Wall surface area was reduced and luminal area was increased in tempol-treated SD and Ren2 rats compared with untreated controls (P Ͻ 0.05). Collectively, the results of this investigation support a seminal role for enhanced tissue RAS/oxidative stress as factors in development of PH and pulmonary vascular remodeling. renin; angiotensin II; NADPH oxidase CARDIOVASCULAR GENERATION of reactive oxygen species (ROS), such as superoxide and H 2 O 2 , has been implicated in the pathogenesis of hypertension, cardiac hypertrophy, pulmonary hypertension (PH), and heart failure (7). Molecular complexes known to generate superoxide within vascular endothelial and smooth muscle cells (SMC) include the NADPH oxidases (18), xanthine oxidase (32), the mitochondrial transport chain, and uncoupled nitric oxide synthase (NOS) (10,19). NADPH oxidase is a major source of ROS in the vasculature and is activated by hormones, growth factors, cytokines, and shear stress (16). An important stimulus for NADPH oxidase-generated ROS is ANG II. In fact, many of the deleterious effects of ANG II on vascular structure and function are mediated by ROS generation (16,73). ANG II causes rapid induction of NADPH oxidase-dependent superoxide synthesis via PKC (15) and more prolonged stimulation via transactivation of growth factors (62, 69). ANG II also causes redox-sensitive xanthine oxidase activation and endothelial N...

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Renin in human fetal lung ??? a biochemical and immunohistochemical study

Cited by 14 publications

References 0 publications

Kidney Is the Only Source of Human Plasma Renin in 45-kb Human Renin Transgenic Mice

Kidney Is the Only Source of Human Plasma Renin in 45-kb Human Renin Transgenic Mice

Angiotensin induces the urinary peristaltic machinery during the perinatal period.

Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat

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