Different effects of angiotensin II and catecholamine on renal cell apoptosis and proliferation in rats

Aizawa, Toru; Ishizaka, Nobukazu; Kurokawa, Kiyoshi; Nagai, Ryozo; Nakajima, Hiroyoshi; Taguchi, Junichi; Ohno, Minoru

doi:10.1046/j.1523-1755.2001.059002645.x

Cited by 43 publications

(35 citation statements)

References 30 publications

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“…In this regard, it is possible that the enhanced PCNA cell number observed in the rats with malignant hypertension reflected increased tubular cell proliferation secondary to tubular dilation induced by glomerular ischemia. In essence, it is possible that glomerular ischemia resulted in tubular cell atrophy and dilation and that the increased PCNA cell number reflected the increased cell proliferation that occurred to repopulate the damaged tubules (1). Further studies are required to address this issue.…”

Section: Discussionmentioning

confidence: 99%

Renal vascular and tubulointerstitial inflammation and proliferation in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension

Graciano

Mouton²,

Patterson³

et al. 2007

American Journal of Physiology-Renal Physiology

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Graciano ML, Mouton CR, Patterson ME, Seth DM, Mullins JJ, Mitchell KD. Renal vascular and tubulointerstitial inflammation and proliferation in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension. Am J Physiol Renal Physiol 292: F1858 -F1866, 2007. First published March 6, 2007;doi:10.1152/ajprenal.00469.2006.-Transgenic rats with inducible ANG II-dependent malignant hypertension [TGR(Cyp1a1Ren2)] were generated by inserting the mouse Ren2 renin gene into the genome of the rat. The present study was performed to assess renal morphological changes occurring during the development of ANG IIdependent malignant hypertension in these rats. Male Cyp1a1-Ren2 rats (n ϭ 10) were fed normal rat food containing indole-3-carbinol (I3C; 0.3%) for 10 days to induce malignant hypertension. Rats induced with I3C had higher mean arterial pressures (173 Ϯ 9 vs. 112 Ϯ 11 mmHg, P Ͻ 0.01) than noninduced normotensive rats (n ϭ 9). Glomerular damage was evaluated by determination of the glomerulosclerosis index (GSI) in tissue sections stained with periodic acid-Schiff. Kidneys of hypertensive rats had a higher GSI than normotensive rats (21.3 Ϯ 5.6 vs. 3.5 Ϯ 1.31 units). Quantitative analysis of macrophage ED-1-positive cells and proliferating cell nuclear antigen using immunohistochemistry demonstrated increased macrophage numbers in the renal interstitium (106.4 Ϯ 11.4 vs. 58.7 Ϯ 5.0 cells/mm 2 ) and increased proliferating cell number in cortical tubules (37.8 Ϯ 5.7 vs. 24.2 Ϯ 2.1 cells/mm 2 ), renal cortical vessels (2.2 Ϯ 0.5 vs. 0.13 Ϯ 0.07 cells/vessel), and the cortical interstitium (33.6 Ϯ 5.7 vs. 4.2 Ϯ 1.4 cells/mm 2 ) of hypertensive rat kidneys. These findings demonstrate that the renal pathological changes that occur during the development of malignant hypertension in Cyp1a1-Ren2 rats are characterized by inflammation and cellular proliferation in cortical vessels and tubulointerstitium. kidney; glomerulosclerosis; renal injury; immunohistochemistry; renin-angiotensin system; renal pathology; peptide hormones TRANSGENIC RATS WITH INDUCIBLE activation of extrarenal renin gene expression [TGR(Cyp1a1Ren2)] were generated using a renin transgene under the transcriptional control of the cytochrome P-450 (Cyp1a1) promoter (23). This transgenic rat line was created by inserting a mouse Ren2 renin gene, fused to an 11.5-kb fragment of the Cyp1a1 promoter, into the genome of the Fischer 344 rat (23). Cyp1a1, which catalyzes the oxidation of a wide range of endogenous lipophilic compounds and xenobiotics (7, 10, 43), is not constitutively expressed but is highly inducible on exposure to various aryl hydrocarbons such as indole-3-carbinol (I3C) (7,10,14,21,26,33,43). Induction of Cyp1a1 is mediated by the aryl hydrocarbon receptor, which is a basic helix-loop-helix-transcription factor that binds to specific DNA elements in the Cyp1a1 promoter (7, 13, 43). Rats transgenic for the Cyp1a1-Ren2 construct do not constitutively express the Ren2 renin gene. Rather, the Ren2 gene is expressed, primarily i...

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Section: Discussionmentioning

confidence: 99%

Renal vascular and tubulointerstitial inflammation and proliferation in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension

Graciano

Mouton²,

Patterson³

et al. 2007

American Journal of Physiology-Renal Physiology

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“…Accordingly, chronic ANG II infusion is extensively used to investigate mechanisms that mediate renal damage in hypertensive states characterized by enhanced RAAS activation (3,20,42,65,71). Renal parenchymal injury with significant tubulointerstitial fibrosis and a propensity to develop salt-sensitive hypertension has been observed after ANG II infusions (44, 57).…”

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confidence: 99%

Blood pressure-renal blood flow relationships in conscious angiotensin II- and phenylephrine-infused rats

Polichnowski

Griffin

Long

et al. 2013

American Journal of Physiology-Renal Physiology

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Polichnowski AJ, Griffin KA, Long J, Williamson GA, Bidani AK. Blood pressure-renal blood flow relationships in conscious angiotensin II-and phenylephrine-infused rats. Am J Physiol Renal Physiol 305: F1074 -F1084, 2013. First published July 3, 2013 doi:10.1152/ajprenal.00111.2013.-Chronic ANG II infusion in rodents is widely used as an experimental model of hypertension, yet very limited data are available describing the resulting blood pressurerenal blood flow (BP-RBF) relationships in conscious rats. Accordingly, male Sprague-Dawley rats (n ϭ 19) were instrumented for chronic measurements of BP (radiotelemetry) and RBF (Transonic Systems, Ithaca, NY). One week later, two or three separate 2-h recordings of BP and RBF were obtained in conscious rats at 24-h intervals, in addition to separate 24-h BP recordings. Rats were then administered either ANG II (n ϭ 11, 125 ng·kg Ϫ1 ·min Ϫ1 ) or phenylephrine (PE; n ϭ 8, 50 mg·kg Ϫ1 ·day Ϫ1 ) as a control, ANG IIindependent, pressor agent. Three days later the BP-RBF and 24-h BP recordings were repeated over several days. Despite similar increases in BP, PE led to significantly greater BP lability at the heart beat and very low frequency bandwidths. Conversely, ANG II, but not PE, caused significant renal vasoconstriction (a 62% increase in renal vascular resistance and a 21% decrease in RBF) and increased variability in BP-RBF relationships. Transfer function analysis of BP (input) and RBF (output) were consistent with a significant potentiation of the renal myogenic mechanism during ANG II administration, likely contributing, in part, to the exaggerated reductions in RBF during periods of BP elevations. We conclude that relatively equipressor doses of ANG II and PE lead to greatly different ambient BP profiles and effects on the renal vasculature when assessed in conscious rats. These data may have important implications regarding the pathogenesis of hypertension-induced injury in these models of hypertension.hypertension; hemodynamics; blood pressure variability INCREASED ACTIVITY OF THE renin-angiotensin-aldosterone system (RAAS) (40,56,73) is postulated to be a major contributor to chronic kidney disease progression through both blood pressure (BP)-dependent and -independent mechanisms (7,28,39,73). Accordingly, chronic ANG II infusion is extensively used to investigate mechanisms that mediate renal damage in hypertensive states characterized by enhanced RAAS activation (3,20,42,65,71). Renal parenchymal injury with significant tubulointerstitial fibrosis and a propensity to develop salt-sensitive hypertension has been observed after ANG II infusions (44, 57). Both barotrauma and renal vasoconstrictionmediated tissue ischemia have been postulated to initiate the pathogenic cascades that lead to renal injury after chronic ANG II infusions. However, despite its wide use, there is a paucity of experimental data describing the BP-renal blood flow (RBF) relationships in conscious ANG II-infused animals, and the relative contribution of these two initiating mechanisms ...

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“…In this regard, a fundamental basis for the injurious effects of ANG II involves the imposition of oxidant stress via NADPH oxidase (35). Studies by us and others have demonstrated that ANG II induces the antioxidant gene heme oxygenase-1 (HO-1) (3,4,11) in the kidney in vivo and in vitro and that such induction of HO-1, by virtue of its antioxidant, anti-inflammatory, and vasorelaxant properties (1,2,15,24), is implicated as an adaptive, protective mechanism that can reduce the severity of ANG II-induced renal injury.…”

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confidence: 99%

“…Such studies demonstrate that ANG II, so administered, provokes markedly increased systemic arterial pressure, reduces glomerular filtration rate (GFR), increases urinary protein excretion, induces the expression of proinflammatory and other damaging genes, and provokes proliferation as well as apoptosis of tubular epithelial cells (3,4,11,36). However, many of these studies, including the initial studies by us and others demonstrating renal induction of HO-1 by ANG II in vivo, have employed pressor dosages/regimens of ANG II that lead to markedly elevated plasma levels of ANG II.…”

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Heme oxygenase activity as a determinant of the renal hemodynamic response to low-dose ANG II

Nath

Hernandez

Croatt

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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II causes renal injury through hemodynamic and other effects, and pressor doses of ANG II induce heme oxygenase-1 (HO-1) as a protective response. The present studies examined the hemodynamic effects of more clinically relevant, lower doses of ANG II and the role of HO activity in influencing these effects. Under euvolemic conditions, ANG II increased arterial pressure and renal vascular resistance. ANG II did not induce oxidative stress, inflammation/injury-related gene expression, or proteinuria and did not alter extrarenal vascular reactivity. At these doses, ANG II failed to increase HO-1 or HO-2 mRNA expression or HO activity. Inhibiting HO activity in ANG II-treated rats by tin mesoporphyrin further increased renal vascular resistances, decreased renal blood flow, and blunted the rise in arterial pressure without inducing oxidative stress or altering expression of selected vasoactive/ injury/inflammation-related genes; tin mesoporphyrin did not alter vasorelaxation of mesenteric resistor vessels. We conclude that in this model renal vasoconstriction occurs without the recognized adverse effects of ANG II on glomerular filtration rate, renal blood flow, oxidative stress, vascular reactivity, proteinuria, and injury-related gene expression; renal HO activity is essential in preserving perfusion of the ANG II-exposed kidney. These findings represent an uncommon example wherein function of a stressed organ (by ANG II), but not that of the unstressed organ, requires intact renal HO activity, even when the imposed stress neither induces HO-1 nor HO activity. These findings may be germane to conditions attended by heightened ANG II levels, ineffective renal perfusion, and susceptibility to acute kidney injury. tin mesoporphyrin; ischemia ANG II IS A MAJOR CONTRIBUTOR to chronic kidney disease by virtue of its hemodynamic, proinflammatory, and profibrotic effects. Indeed, agents that interrupt the generation of ANG II and the engagement of ANG II with its receptor comprise a fundamental therapeutic approach in the management of patients with chronic kidney disease (12,20,22). Such therapies, however, reduce but do not abort the progression of chronic kidney disease, and thus complementary strategies that can synergize with these therapies would be of interest. In this regard, a fundamental basis for the injurious effects of ANG II involves the imposition of oxidant stress via NADPH oxidase (35). Studies by us and others have demonstrated that ANG II induces the antioxidant gene heme oxygenase-1 (HO-1) (3, 4, 11) in the kidney in vivo and in vitro and that such induction of HO-1, by virtue of its antioxidant, anti-inflammatory, and vasorelaxant properties (1,2,15,24), is implicated as an adaptive, protective mechanism that can reduce the severity of ANG II-induced renal injury.An established approach employed in studying the pathogenetic basis for ANG II-induced renal injury utilizes the chronic administration of ANG II by osmotic minipumps. Such studies demonstrate that ANG II, so administered, provokes markedly i...

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Different effects of angiotensin II and catecholamine on renal cell apoptosis and proliferation in rats

Abstract: These data suggest that Ang II plays a pivotal role in the development of renal cell proliferation and apoptosis in the setting of hypertension. The renal HO system may modulate proliferative and pro-apoptotic effects of Ang II.

Cited by 43 publications

References 30 publications

Renal vascular and tubulointerstitial inflammation and proliferation in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension

Renal vascular and tubulointerstitial inflammation and proliferation in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension

Blood pressure-renal blood flow relationships in conscious angiotensin II- and phenylephrine-infused rats

Heme oxygenase activity as a determinant of the renal hemodynamic response to low-dose ANG II

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