Oral Treatment with Angiotensin-(1-7) Attenuates the Kidney Injury Induced by Gentamicin in Wistar Rats

2021 ◽  
Vol 28 ◽  
Author(s):  
Lílian Fernanda Pacheco ◽  
Carlos Henrique de Castro ◽  
João Batista Rodrigues Dutra ◽  
Ruy de Souza Lino Junior ◽  
Patrícia Maria Ferreira ◽  
...  
Keyword(s):  
Oral Treatment ◽  
Subcutaneous Administration ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Fractional Excretion ◽  
Function Evaluation ◽  
Common Disease ◽  
Urinary Flow ◽  
Ang Ii ◽  
Renal Injuries

Background: Acute Kidney Injury (AKI), a common disease of the urinary system, can be induced by high doses of gentamicin (GM). The Renin-Angiotensin System exerts a key role in the progression of the AKI since elevated intrarenal levels of Ang II, and ACE activity is found in this condition. However, it is unknown whether oral administration of Ang-(1-7), a heptapeptide that evokes opposite effects of Ang II, may attenuate the renal injuries induced by gentamicin. Objectives: To evaluate the effects of Ang (1-7) on GM-induced renal dysfunction in rats. Methods: AKI was induced by subcutaneous administration of GM (80 mg/Kg) for 5 days. Simultaneously, Ang-(1-7) included in hydroxypropyl β-cyclodextrin (HPβCD) was administered by gavage [46 μg/kg HPβCD + 30 μg/kg Ang- (1-7)]. At the end of the treatment period (sixth day), the rats were housed in metabolic cages for renal function evaluation. Thereafter, blood and kidney samples were collected. Results: The Ang-(1-7) attenuated the increase of the plasmatic creatinine and proteinuria caused by GM but did not change the glomerular filtration rate nor tubular necrosis. Ang-(1-7) attenuated the increased urinary flow and the fractional excretion of H2O and potassium observed in GM rats but intensified the elevated excretion of sodium in these animals. Morphological analysis showed that Ang-(1-7) also reduced the tubular vacuolization in kidneys from GM rats. Conclusion: Ang-(1-7) promotes selective beneficial effects in renal injuries induced by GM.

scholarly journals AT1 and AT2 receptors modulate renal tubular cell necroptosis in angiotensin II-infused renal injury mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yongjun Zhu ◽  
Hongwang Cui ◽  
Jie Lv ◽  
Haiqin Liang ◽  
Yanping Zheng ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Critical Role ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Tubular Cell ◽  
Tubular Damage ◽  
Renal Tubular Cell ◽  
Ang Ii ◽  
Renal Tubular

AbstractAbnormal renin-angiotensin system (RAS) activation plays a critical role in the initiation and progression of chronic kidney disease (CKD) by directly mediating renal tubular cell apoptosis. Our previous study showed that necroptosis may play a more important role than apoptosis in mediating renal tubular cell loss in chronic renal injury rats, but the mechanism involved remains unknown. Here, we investigate whether blocking the angiotensin II type 1 receptor (AT1R) and/or angiotensin II type 2 receptor (AT2R) beneficially alleviates renal tubular cell necroptosis and chronic kidney injury. In an angiotensin II (Ang II)-induced renal injury mouse model, we found that blocking AT1R and AT2R effectively mitigates Ang II-induced increases in necroptotic tubular epithelial cell percentages, necroptosis-related RIP3 and MLKL protein expression, serum creatinine and blood urea nitrogen levels, and tubular damage scores. Furthermore, inhibition of AT1R and AT2R diminishes Ang II-induced necroptosis in HK-2 cells and the AT2 agonist CGP42112A increases the percentage of necroptotic HK-2 cells. In addition, the current study also demonstrates that Losartan and PD123319 effectively mitigated the Ang II-induced increases in Fas and FasL signaling molecule expression. Importantly, disruption of FasL significantly suppressed Ang II-induced increases in necroptotic HK-2 cell percentages, and necroptosis-related proteins. These results suggest that Fas and FasL, as subsequent signaling molecules of AT1R and AT2R, might involve in Ang II-induced necroptosis. Taken together, our results suggest that Ang II-induced necroptosis of renal tubular cell might be involved both AT1R and AT2R and the subsequent expression of Fas, FasL signaling. Thus, AT1R and AT2R might function as critical mediators.

scholarly journals ACE2 Shedding and the Role in COVID-19

2022 ◽  
Vol 11 ◽  
Author(s):  
Jieqiong Wang ◽  
Huiying Zhao ◽  
Youzhong An
Keyword(s):  
Amino Acids ◽  
Viral Entry ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Underlying Mechanism ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Transmembrane Glycoprotein

Angiotensin converting enzyme 2 (ACE2), a transmembrane glycoprotein, is an important part of the renin-angiotensin system (RAS). In the COVID-19 epidemic, it was found to be the receptor of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). ACE2 maintains homeostasis by inhibiting the Ang II-AT1R axis and activating the Ang I (1-7)-MasR axis, protecting against lung, heart and kidney injury. In addition, ACE2 helps transport amino acids across the membrane. ACE2 sheds from the membrane, producing soluble ACE2 (sACE2). Previous studies have pointed out that sACE2 plays a role in the pathology of the disease, but the underlying mechanism is not yet clear. Recent studies have confirmed that sACE2 can also act as the receptor of SARS-COV-2, mediating viral entry into the cell and then spreading to the infective area. Elevated concentrations of sACE2 are more related to disease. Recombinant human ACE2, an exogenous soluble ACE2, can be used to supplement endogenous ACE2. It may represent a potent COVID-19 treatment in the future. However, the specific administration concentration needs to be further investigated.

Abstract 188: Loss of Renal Prolyl Carboxypeptidase in Mice With Chronic Kidney Disease

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Orly Leiva ◽  
Khalid M Elased ◽  
Mariana Morris ◽  
Nadja Grobe
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Protein Expression ◽  
Western Blot ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Left Renal Artery ◽  
Renal Tubules ◽  
Ang Ii ◽  
Chronic Kidney Injury

There are 26 million adults with chronic kidney disease (CKD) in the U.S. and the incidence continues to increase. It is well documented that the activation of the renin angiotensin system and the elevated formation of angiotensin (Ang) II both contribute to renal pathophysiology in CKD. Emerging evidence suggests that the Ang II degrading protease prolyl carboxypeptidase (PCP) is renoprotective. Thus, we investigated protein expression and activity of renal PCP using immunofluorescence, western blot and mass spectrometry in a mouse model of CKD. Renal injury in male C57Bl6 mice was caused by constriction of the left renal artery using silver clips (2K1C-method). Blood pressure measurements by radiotelemetry revealed a significant increase of 36.1 ± 3.9 mm Hg in 2K1C animals compared with control animals 1 week after clip placement (p<0.0001). Using immunofluorescence and confocal microscopy, PCP was localized in the Bowman’s capsule of the glomerulus and in proximal and distal renal tubules. Western blot analysis showed PCP was significantly reduced in clipped 2K1C kidneys compared to unclipped kidneys of the 2K1C mice or compared to control mice (clipped 0.04 ± 0.02 vs unclipped 0.58 ± 0.16 vs control 0.65 ± 0.18, p < 0.05). In addition, renal PCP enzyme activity was found to be markedly reduced in 2K1C kidneys as assessed by mass spectrometric based enzyme assays (clipped 37.1 ± 4.3 pmol Ang-(1-7)/h/μg vs unclipped 77.3 ± 12.3 pmol Ang-(1-7)/h/μg vs control 120.7 ± 14.7 pmol Ang-(1-7)/h/μg, p < 0.01). In contrast, protein expression of prolyl endopeptidase, another enzyme capable of converting Ang II into Ang-(1-7), was not affected. Notably, renal pathologies were exacerbated in the 2K1C model as revealed by a significant increase in mesangial expansion (clipped 34.6 ± 3.1 vs unclipped 52.1 ± 4.0 vs control 1.2 ± 2.1, p < 0.0001) and renal fibrosis (clipped 57.5 ± 0.9 vs unclipped 33.0 ± 0.7 vs control 3.3 ± 0.2, p < 0.0001). Results suggest that PCP is suppressed in chronic kidney injury and that this downregulation may attenuate renoprotective effects via impaired Ang II degradation by PCP. Therefore, Ang II processing by PCP may have clinical implications in patients with renal pathologies.

Enhanced intrarenal receptor-mediated prorenin activation in chronic progressive anti-thymocyte serum nephritis rats on high salt intake

2012 ◽  
Vol 303 (1) ◽  
pp. F130-F138 ◽  
Author(s):  
Yanjie Huang ◽  
Tatsuo Yamamoto ◽  
Taro Misaki ◽  
Hiroyuki Suzuki ◽  
Akashi Togawa ◽  
...  
Keyword(s):  
Apical Membrane ◽  
Salt Intake ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
High Salt ◽  
Ang Ii ◽  
Kidney Fibrosis ◽  
High Salt Intake ◽  
Collecting Ducts

Despite suppression of the circulating renin-angiotensin system (RAS), high salt intake (HSI) aggravates kidney injury in chronic kidney disease. To elucidate the effect of HSI on intrarenal RAS, we investigated the levels of intrarenal prorenin, renin, (pro)renin receptor (PRR), receptor-mediated prorenin activation, and ANG II in chronic anti-thymocyte serum (ATS) nephritic rats on HSI. Kidney fibrosis grew more severe in the nephritic rats on HSI than normal salt intake. Despite suppression of plasma renin and ANG II, marked increases in tubular prorenin and renin proteins without concomitant rises in renin mRNA, non-proteolytically activated prorenin, and ANG II were noted in the nephritic rats on HSI. Redistribution of PRR from the cytoplasm to the apical membrane, along with elevated non-proteolytically activated prorenin and ANG II, was observed in the collecting ducts and connecting tubules in the nephritic rats on HSI. Olmesartan decreased cortical prorenin, non-proteolytically activated prorenin and ANG II, and apical membranous PRR in the collecting ducts and connecting tubules, and attenuated the renal lesions. Cell surface trafficking of PRR was enhanced by ANG II and was suppressed by olmesartan in Madin-Darby canine kidney cells. These data suggest the involvement of the ANG II-dependent increase in apical membrane PRR in the augmentation of intrarenal binding of prorenin and renin, followed by nonproteolytic activation of prorenin, enhancement of renin catalytic activity, ANG II generation, and progression of kidney fibrosis in the nephritic rat kidneys on HSI. The origin of the increased tubular prorenin and renin remains to be clarified. Further studies measuring the urinary prorenin and renin are needed.

Renal nerve stimulation leads to the activation of the Na+/H+ exchanger isoform 3 via angiotensin II type I receptor

2015 ◽  
Vol 308 (8) ◽  
pp. F848-F856 ◽  
Author(s):  
Roberto B. Pontes ◽  
Renato O. Crajoinas ◽  
Erika E. Nishi ◽  
Elizabeth B. Oliveira-Sales ◽  
Adriana C. Girardi ◽  
...  
Keyword(s):  
Nerve Stimulation ◽  
Low Frequency ◽  
Renin Angiotensin System ◽  
Receptor Activation ◽  
Sodium Reabsorption ◽  
Urinary Flow ◽  
Type I ◽  
Ang Ii ◽  
Renal Nerve ◽  
Renal Nerve Stimulation

Renal nerve stimulation at a low frequency (below 2 Hz) causes water and sodium reabsorption via α1-adrenoreceptor tubular activation, a process independent of changes in systemic blood pressure, renal blood flow, or glomerular filtration rate. However, the underlying mechanism of the reabsorption of sodium is not fully understood. Since the sympathetic nervous system and intrarenal ANG II appear to act synergistically to mediate the process of sodium reabsorption, we hypothesized that low-frequency acute electrical stimulation of the renal nerve (ESRN) activates NHE3-mediated sodium reabsorption via ANG II AT1 receptor activation in Wistar rats. We found that ESRN significantly increased urinary angiotensinogen excretion and renal cortical ANG II content, but not the circulating angiotensinogen levels, and also decreased urinary flow and pH and sodium excretion via mechanisms independent of alterations in creatinine clearance. Urinary cAMP excretion was reduced, as was renal cortical PKA activity. ESRN significantly increased NHE3 activity and abundance in the apical microvillar domain of the proximal tubule, decreased the ratio of phosphorylated NHE3 at serine 552/total NHE3, but did not alter total cortical NHE3 abundance. All responses mediated by ESRN were completely abolished by a losartan-mediated AT1 receptor blockade. Taken together, our results demonstrate that higher NHE3-mediated proximal tubular sodium reabsorption induced by ESRN occurs via intrarenal renin angiotensin system activation and triggering of the AT1 receptor/inhibitory G-protein signaling pathway, which leads to inhibition of cAMP formation and reduction of PKA activity.

scholarly journals Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes

2012 ◽  
Vol 302 (11) ◽  
pp. F1374-F1384 ◽  
Author(s):  
Liliya M. Yamaleyeva ◽  
Shea Gilliam-Davis ◽  
Igor Almeida ◽  
K. Bridget Brosnihan ◽  
Sarah H. Lindsey ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Ang Ii ◽  
Similar Extent ◽  
Early Diabetes ◽  
Renal Inflammation ◽  
Angiotensin Converting Enzyme 2 ◽  
Reactive Protein ◽  
Blood Pressures ◽  
The Impact

We examined the impact of early diabetes on the circulating and kidney renin-angiotensin system (RAS) in male and female mRen2.Lewis (mRen2) hypertensive rats. Diabetes (DB) was induced by streptozotocin (STZ; 65 mg/kg) at 11 wk of age for 4 wk without insulin replacement. Systolic blood pressures were not increased in DB males or females compared with controls (CON). Circulating angiotensin-converting enzyme 2 (ACE2) increased ninefold ( P < 0.05) in DB females and threefold ( P < 0.05) in DB males, but circulating ACE and ANG II were higher in the DB groups. Serum C-reactive protein was elevated in DB females but not DB males, and the vascular responses to acetylcholine and estradiol were attenuated in the DB females. Proteinuria, albuminuria, and angiotensinogen excretion increased to a similar extent in both DB females and males. Glomerular VEGF expression also increased to a similar extent in both DB groups. Renal inflammation (CD68+cells) increased only in DB females although males exhibited greater inflammation that was not different with DB. Cortical ACE2 did not change in DB females but was reduced (30%) in DB males. Renal neprilysin activity (>75%, P < 0.05) was markedly reduced in the DB females to that in the DB and CON males. ACE activity was significantly lower in both female (75%, P < 0.05) and male (50%; P < 0.05) DB groups, while cortical ANG II and Ang-(1-7) levels were unchanged. In conclusion, female mRen2 rats are not protected from vascular damage, renal inflammation, and kidney injury in early STZ-induced diabetes despite a marked increase in circulating ACE2 and significantly reduced ACE within the kidney.

scholarly journals Stimulation of lymphocyte responses by angiotensin II promotes kidney injury in hypertension

2008 ◽  
Vol 295 (2) ◽  
pp. F515-F524 ◽  
Author(s):  
Steven D. Crowley ◽  
Campbell W. Frey ◽  
Samantha K. Gould ◽  
Robert Griffiths ◽  
Phillip Ruiz ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Cardiac Hypertrophy ◽  
Transforming Growth Factor ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Transforming Growth Factor Β ◽  
Ang Ii ◽  
Lymphocyte Responses ◽  
Stimulation Of

Activation of the renin-angiotensin system contributes to the progression of chronic kidney disease. Based on the known cellular effects of ANG II to promote inflammation, we posited that stimulation of lymphocyte responses by ANG II might contribute to the pathogenesis of hypertensive kidney injury. We therefore examined the effects of the immunosuppressive agent mycophenolate mofetil (MMF) on the course of hypertension and kidney disease induced by chronic infusion of ANG II in 129/SvEv mice. Although it had no effect on the severity of hypertension or cardiac hypertrophy, treatment with MMF significantly reduced albuminuria and ameliorated kidney injury, decreasing glomerulosclerosis and reducing lymphocyte infiltration into the renal interstitium. Attenuation of renal pathology with MMF was associated with reduced expression of mRNAs for the proinflammatory cytokines interferon-γ and tumor necrosis factor-α and the profibrotic cytokine transforming growth factor-β. As infiltration of the kidney by T lymphocytes was a prominent feature of ANG II-dependent renal injury, we carried out experiments examining the effects of ANG II on lymphocytes in vitro. We find that exposure of splenic lymphocytes to ANG II causes prominent rearrangements of the actin cytoskeleton. These actions require the activity of Rho kinase. Thus, ANG II exaggerates hypertensive kidney injury by stimulating lymphocyte responses. These proinflammatory actions of ANG II seem to have a proclivity for inducing kidney injury while having negligible actions in the pathogenesis of cardiac hypertrophy.

scholarly journals Angiotensin-(1-7)—A Potential Remedy for AKI: Insights Derived from the COVID-19 Pandemic

2021 ◽  
Vol 10 (6) ◽  
pp. 1200
Author(s):  
Samuel N. Heyman ◽  
Thomas Walther ◽  
Zaid Abassi
Keyword(s):  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Host Cells ◽  
Ang Ii ◽  
Viral Attachment ◽  
Beneficial Effects ◽  
Membrane Bound ◽  
G Protein Coupled ◽  
Parenchymal Damage

Membrane-bound angiotensin converting enzyme (ACE) 2 serves as a receptor for the Sars-CoV-2 spike protein, permitting viral attachment to target host cells. The COVID-19 pandemic brought into light ACE2, its principal product angiotensin (Ang) 1-7, and the G protein-coupled receptor for the heptapeptide (MasR), which together form a still under-recognized arm of the renin–angiotensin system (RAS). This axis counteracts vasoconstriction, inflammation and fibrosis, generated by the more familiar deleterious arm of RAS, including ACE, Ang II and the ang II type 1 receptor (AT1R). The COVID-19 disease is characterized by the depletion of ACE2 and Ang-(1-7), conceivably playing a central role in the devastating cytokine storm that characterizes this disorder. ACE2 repletion and the administration of Ang-(1-7) constitute the therapeutic options currently tested in the management of severe COVID-19 disease cases. Based on their beneficial effects, both ACE2 and Ang-(1-7) have also been suggested to slow the progression of experimental diabetic and hypertensive chronic kidney disease (CKD). Herein, we report a further step undertaken recently, utilizing this type of intervention in the management of evolving acute kidney injury (AKI), with the expectation of renal vasodilation and the attenuation of oxidative stress, inflammation, renal parenchymal damage and subsequent fibrosis. Most outcomes indicate that triggering the ACE2/Ang-(1-7)/MasR axis may be renoprotective in the setup of AKI. Yet, there is contradicting evidence that under certain conditions it may accelerate renal damage in CKD and AKI. The nature of these conflicting outcomes requires further elucidation.

Renal responses to hypoxemia during renin-angiotensin system inhibition in fetal lambs

1985 ◽  
Vol 249 (1) ◽  
pp. R116-R124 ◽  
Author(s):  
K. T. Nakamura ◽  
N. A. Ayres ◽  
R. A. Gomez ◽  
J. E. Robillard
Keyword(s):  
Renin Angiotensin System ◽  
Base Line ◽  
Urinary Flow ◽  
Ang Ii ◽  
Functional Responses ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Arterial Blood ◽  
Renal Hemodynamic ◽  
Excretion Rates

The role of the renin-angiotensin system (RAS) in modulating the renal hemodynamic and functional responses to hypoxemia was studied in chronically catheterized fetal lambs (132-143 days gestation; term 145 days) before and during administration of either captopril or [Sar1-Gly8]ANG II. Base-line mean arterial blood pressure decreased significantly after administration of either captopril or [Sar1-Gly8]ANG II. This decrease was associated with a significant decline in renal vascular resistance (RVR) in captopril-treated fetuses, whereas no changes in RVR were observed in [Sar1-Gly8]ANG II-treated fetuses. However, the decline in renal blood flow (RBF) and the rise in RVR associated with hypoxemia in control fetuses were not attenuated significantly during inhibition of the RAS using either captopril or [Sar1-Gly8]ANG II. Moreover neither captopril nor [Sar1-Gly8]ANG II blunted the hypertensive response associated with fetal hypoxemia. The renal functional response to captopril was different from the response observed during infusion of [Sar1-Gly8]ANG II. Administration of [Sar1-Gly8]ANG II produced significant decreases in urinary flow rate (UFR), glomerular filtration rate (GFR), and urinary electrolyte (Na+, K+, Cl-) excretion rates, whereas no changes were observed during captopril infusion. The effects of hypoxemia on renal function were not modified after captopril. However, [Sar1-Gly8]ANG II tended to increase UFR and GFR, but these changes were pressure-dependent and not directly related to inhibition of the RAS. This study suggests that the RAS is not an important mediator of the fetal renal hemodynamic and functional responses to hypoxemia.

Activation of renal renin-angiotensin system in upstream stimulatory factor 2 transgenic mice

2009 ◽  
Vol 296 (2) ◽  
pp. F257-F265 ◽  
Author(s):  
Lihua Shi ◽  
Dejan Nikolic ◽  
Shu Liu ◽  
Hong Lu ◽  
Shuxia Wang
Keyword(s):  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Renal Diseases ◽  
Ang Ii ◽  
Upstream Stimulatory Factor ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Stimulatory Factor

Previously we demonstrated that upstream stimulatory factor 2 (USF2) transgenic (Tg) mice developed nephropathy including albuminuria and glomerular hypertrophy, accompanied by increased transforming growth factor (TGF)-β and fibronectin accumulation in the glomeruli. However, the mechanisms by which overexpression of USF2 induces kidney injury are unknown. USF has been shown to regulate renin expression. Moreover, the renin-angiotensin system (RAS) plays important roles in renal diseases. Therefore, in the present studies the effects of USF2 on the regulation of RAS in the kidney as well as in mesangial cells from USF2 (Tg) mice were examined. The role of USF2-mediated regulation of RAS in TGF-β production in mesangial cells was also determined. Our data demonstrate that USF2 (Tg) mice exhibit increased renin and angiotensin (ANG) II levels in the kidney. In contrast, renal expression of other components of RAS such as renin receptor, angiotensinogen, angiotensin-converting enzyme (ACE), ACE2, angiotensin type 1a (AT1a) receptor, and AT2 receptor was not altered in USF2 (Tg) mice. Similarly, mesangial cells isolated from USF2 (Tg) mice had increased renin and ANG II levels. Mesangial cells overexpressing USF2 also had increased TGF-β production, which was blocked by small interfering RNA-mediated renin gene knockdown or RAS blockade (enalapril or losartan). Collectively, these results suggest that USF2 promotes renal renin expression and stimulates ANG II generation, leading to activation of the intrarenal RAS. In addition, renin-dependent ANG II generation mediates the effect of USF2 on TGF-β production in mesangial cells, which may contribute to the development of nephropathy in USF2 (Tg) mice.

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