Involvement of glomerular renin−angiotensin system (RAS) activation in the development and progression of glomerular injury

Sympathetic hyperactivity (SH) and renin angiotensin system (RAS) activation are commonly associated with heart failure (HF), even though the relative contribution of these factors to the cardiac derangement is less understood. The role of SH on RAS components and its consequences for the HF were investigated in mice lacking α2A and α2C adrenoceptor knockout (α2A/α2CARKO) that present SH with evidence of HF by 7 mo of age. Cardiac and systemic RAS components and plasma norepinephrine (PN) levels were evaluated in male adult mice at 3 and 7 mo of age. In addition, cardiac morphometric analysis, collagen content, exercise tolerance, and hemodynamic assessments were made. At 3 mo, α2A/α2CARKO mice showed no signs of HF, while displaying elevated PN, activation of local and systemic RAS components, and increased cardiomyocyte width (16%) compared with wild-type mice (WT). In contrast, at 7 mo, α2A/α2CARKO mice presented clear signs of HF accompanied only by cardiac activation of angiotensinogen and ANG II levels and increased collagen content (twofold). Consistent with this local activation of RAS, 8 wk of ANG II AT1 receptor blocker treatment restored cardiac structure and function comparable to the WT. Collectively, these data provide direct evidence that cardiac RAS activation plays a major role underlying the structural and functional abnormalities associated with a genetic SH-induced HF in mice.

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Free Fatty Acids Activate Renin-Angiotensin System in 3T3-L1 Adipocytes through Nuclear Factor-kappa B Pathway

Journal of Diabetes Research ◽

10.1155/2016/1587594 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 8

Author(s):

Jia Sun ◽

Jinhua Luo ◽

Yuting Ruan ◽

Liangchang Xiu ◽

Bimei Fang ◽

...

Keyword(s):

Adipose Tissue ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Renin Angiotensin System ◽

Toll Like Receptor 4 ◽

Angiotensin System ◽

Renin Angiotensin ◽

Ras Activation ◽

Tlr4 Signaling Pathway

The activity of a local renin-angiotensin system (RAS) in the adipose tissue is closely associated with obesity-related diseases. However, the mechanism of RAS activation in adipose tissue is still unknown. In the current study, we found that palmitic acid (PA), one kind of free fatty acid, induced the activity of RAS in 3T3-L1 adipocytes. In the presence of fetuin A (Fet A), PA upregulated the expression of angiotensinogen (AGT) and angiotensin type 1 receptor (AT1R) and stimulated the secretion of angiotensin II (ANG II) in 3T3-L1 adipocytes. Moreover, the activation of RAS in 3T3-L1 adipocytes was blocked when we blocked Toll-like receptor 4 (TLR4) signaling pathway using TAK242 or NF-κB signaling pathway using BAY117082. Together, our results have identified critical molecular mechanisms linking PA/TLR4/NF-κB signaling pathway to the activity of the local renin-angiotensin system in adipose tissue.

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miR-6869-5p Transported by Plasma Extracellular Vesicles Mediates Renal Tubule Injury and Renin-Angiotensin System Activation in Obesity

Frontiers in Medicine ◽

10.3389/fmed.2021.725598 ◽

2021 ◽

Vol 8 ◽

Author(s):

Huan-Huan Liu ◽

Xia-Qing Li ◽

Jin-Feng Liu ◽

Shuang Cui ◽

Han Liu ◽

...

Keyword(s):

Kidney Disease ◽

Renal Tubule ◽

Renin Angiotensin System ◽

Tubular Damage ◽

Tubular Injury ◽

Renal Tubular Damage ◽

Angiotensin System ◽

Renin Angiotensin ◽

Ras Activation ◽

Renal Tubular

Obesity increases the risk of other diseases, including kidney disease. Local renal tubular renin-angiotensin system (RAS) activation may play a role in obesity-associated kidney disease. Extracellular vehicles (EVs) transmit necessary information in obesity and cause remote organ damage, but the mechanism is unclear. The aim of the study was to investigate whether the plasma EVs cargo miR-6869-5p causes RAS activation and renal tubular damage. We isolated plasma EVs from obese and lean subjects and analyzed differentially-expressed miRNAs using RNA-seq. Then, EVs were co-cultured with human proximal renal tubular epithelial cells (PTECs) in vitro. Immunohistochemical pathology was used to assess the degree of RAS activation and tubule injury in vivo. The tubule damage-associated protein and RAS activation components were detected by Western blot. Obesity led to renal tubule injury and RAS activation in humans and mice. Obese-EVs induce RAS activation and renal tubular injury in PTECs. Importantly, miR-6869-5p-treated PTECs caused RAS activation and renal tubular injury, similar to Obese-EVs. Inhibiting miR-6869-5p decreased RAS activation and renal tubular damage. Our findings indicate that plasma Obese-EVs induce renal tubule injury and RAS activation via miR-6869-5p transport. Thus, miR-6869-5p in plasma Obese-EVs could be a therapeutic target for local RAS activation in obesity-associated kidney disease.

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Abstract P205: Endothelium-specific Interference with PPARG Causes Cerebral Vascular Dysfunction in Response to Endogenous Renin-angiotensin System Activation

Hypertension ◽

10.1161/hyp.68.suppl_1.p205 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Anand R Nair ◽

Masashi Mukohda ◽

Larry N Agbor ◽

Chunyan Hu ◽

Jing Wu ◽

...

Keyword(s):

Carotid Artery ◽

Basilar Artery ◽

Vascular Dysfunction ◽

Renin Angiotensin System ◽

Dominant Negative ◽

Angiotensin System ◽

Salt Diet ◽

Renin Angiotensin ◽

Ras Activation ◽

Low Salt

Abnormal activation of the endogenous renin-angiotensin system (RAS) has been implicated in various cardiovascular (CV) disorders including hypertension, atherosclerosis and stroke. Whereas a low salt diet may be beneficial in salt-sensitive hypertension, it has been proposed to also cause CV risk due to activation of the RAS. The molecular mechanism by which RAS activation mediates vascular dysfunction remains undefined. Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor which activates anti-oxidant and anti-inflammatory processes and can regulate the actions of angiotensin II (AngII) in the vasculature. We examined endothelial function in transgenic mice specifically expressing dominant-negative (DN) mutations in PPARγ in the endothelium (E-V290M) fed a low salt diet to test the hypothesis that endothelial PPARγ plays a protective role in the vasculature in response to endogenous RAS activation. Circulating levels of renin were significantly increased in both non-transgenic (NT) and E-V290M mice fed a low-salt diet for 6 weeks compared to standard chow (NT: 39.3±7.4 vs 19.8±1.3 ng/ml; E-V290M: 34.3±0.8 vs 16.0±3.8 ng/ml, p<0.05, n=5). Under baseline conditions, responses to endothelium-dependent agonist acetylcholine were not affected in E-V290M mice compared to NT (basilar artery: 66.1±11.8 vs 63.5±3.7%; carotid artery: 93.3±3.6 vs 91.1±4.2%, n=5). Six weeks of low-salt diet significantly impaired acetylcholine-mediated dilation in the basilar artery of E-V290M mice but not in NT (41.7±7.7 vs 74.2±5.0%, p<0.05, n=5). Unlike basilar artery, 6 weeks of low salt diet was not sufficient to induce vascular dysfunction in carotid artery or aorta of E-V290M mice (carotid artery: 85.6±4.4 vs 91.9±2.5%, n=5; aorta: 80.8±5.4 vs 87.0±5.6%, n=3). The responses to endothelium-independent vasodilator sodium nitroprusside (SNP) were not different in E-V290M mice compared to NT controls. We conclude that endothelial-specific interference with PPARγ causes endothelial dysfunction in response to endogenous RAS activation induced by a low-salt diet. Moreover, the cerebral circulation is particularly susceptible to low salt diet-induced dysfunction in conjunction with PPARγ impairment.

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Low-protein diet supplemented with ketoacids ameliorates proteinuria in 3/4 nephrectomised rats by directly inhibiting the intrarenal renin–angiotensin system

British Journal Of Nutrition ◽

10.1017/s0007114516003536 ◽

2016 ◽

Vol 116 (9) ◽

pp. 1491-1501 ◽

Cited By ~ 6

Author(s):

Jia-ying Zhang ◽

Ying Yin ◽

Li Ni ◽

Quan Long ◽

Li You ◽

...

Keyword(s):

Mesangial Cells ◽

Renin Angiotensin System ◽

Renal Haemodynamics ◽

Protein Diet ◽

Low Protein Diet ◽

Angiotensin System ◽

Renin Angiotensin ◽

Low Protein ◽

Ras Activation ◽

Intrarenal Ras

AbstractLow-protein diet plus ketoacids (LPD+KA) has been reported to decrease proteinuria in patients with chronic kidney diseases (CKD). However, the mechanisms have not been clarified. As over-activation of intrarenal renin–angiotensin system (RAS) has been shown to play a key role in the progression of CKD, the current study was performed to investigate the direct effects of LPD+KA on intrarenal RAS, independently of renal haemodynamics. In this study, 3/4 subtotal renal ablated rats were fed 18 % normal-protein diet (Nx-NPD), 6 % low-protein diet (Nx-LPD) or 5 % low-protein diet plus 1 % ketoacids (Nx-LPD+KA) for 12 weeks. Sham-operated rats fed NPD served as controls. The level of proteinuria and expression of renin, angiotensin II (AngII) and its type 1 receptors (AT1R) in the renal cortex were markedly higher in Nx-NPD group than in the sham group. LPD+KA significantly decreased the proteinuria and inhibited intrarenal RAS activation. To exclude renal haemodynamic impact on intrarenal RAS, the serum samples derived from the different groups were added to the culture medium of mesangial cells. It showed that the serum from Nx-NPD directly induced higher expression of AngII, AT1R, fibronectin and transforming growth factor-β1 in the mesangial cells than in the control group. Nx-LPD+KA serum significantly inhibited these abnormalities. Then, proteomics and biochemical detection suggested that the mechanisms underlying these beneficial effects of LPD+KA might be amelioration of the nutritional metabolic disorders and oxidative stress. In conclusion, LPD+KA could directly inhibit the intrarenal RAS activation, independently of renal haemodynamics, thus attenuating the proteinuria in CKD rats.

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Renal renin-angiotensin system in diabetes: functional, immunohistochemical, and molecular biological correlations

AJP Renal Physiology ◽

10.1152/ajprenal.1993.265.4.f477 ◽

1993 ◽

Vol 265 (4) ◽

pp. F477-F486 ◽

Cited By ~ 44

Author(s):

S. Anderson ◽

F. F. Jung ◽

J. R. Ingelfinger

Keyword(s):

Renin Angiotensin System ◽

Plasma Renin ◽

Hydraulic Pressure ◽

Ang Ii ◽

Glomerular Injury ◽

Renal Vasculature ◽

Angiotensin System ◽

Renin Angiotensin ◽

Ace Activity ◽

Immunohistochemical Studies

Recent evidence indicates a role for the renin-angiotensin system (RAS) in the pathogenesis of glomerular injury in diabetes. To further explore the RAS in diabetes, studies were conducted in nondiabetic control rats and in moderately hyperglycemic diabetic (DM) rats. In DM rats, both acute and chronic therapy with the specific angiotensin II (ANG II) receptor antagonist losartan did not affect glomerular hyperfiltration or hyperperfusion but selectively normalized the glomerular capillary hydraulic pressure and ultrafiltration coefficient. To determine the basis of intrarenal hemodynamic responsiveness to RAS inhibition, we conducted biochemical, molecular biological, and immunohistochemical studies to assess endogenous RAS activity. Values for plasma renin concentration and serum angiotensin-converting enzyme (ACE) activity in DM rats were normal. In contrast, intrarenal renin protein content, and renin and angiotensinogen mRNAs, were increased in DM rats, suggesting disproportionate activation of the intrarenal RAS. Total renal ACE activity was significantly reduced in DM rats, but immunohistochemical studies indicated redistribution of ACE in the diabetic kidney. Proximal tubule ACE activity was reduced, but ACE immunostaining intensity was enhanced in glomeruli and renal vasculature. Together, these observations indicate increased RAS activity in those sites (glomeruli and vasculature) most likely to regulate hemodynamic function, potentially explaining the prominent responses to pharmacological blockade of ANG II formation and/or action.

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Renin-Angiotensin System Inhibitors in COVID-19: Current Concepts

International Journal of Hypertension ◽

10.1155/2020/1025913 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Kunal Mahajan ◽

Prakash Chand Negi ◽

Neeraj Ganju ◽

Sachin Sondhi ◽

Naresh Gaur ◽

...

Keyword(s):

Renin Angiotensin System ◽

Protective Role ◽

Current Data ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Ras Activation ◽

Functional Receptor ◽

Ras Inhibitors

The functional receptor to SARS-CoV-2, the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, is angiotensin-converting enzyme-2 (ACE-2), the same enzyme that physiologically counters the renin-angiotensin system (RAS) activation. Some researchers have questioned RAS inhibitors’ safety in COVID-19 patients since these drugs have demonstrated an increase in ACE-2 expression in preclinical studies; therefore, they may facilitate viral invasion. On the contrary, others have hypothesized a protective role of RAS inhibitors against COVID-19-associated lung injury. Overall, the data are grossly inadequate to reach any conclusion since no human trials have yet evaluated the effects of RAS inhibitors in COVID-19. We review the current data and pathophysiological mechanisms behind this intriguing interplay between the RAS inhibitors and the COVID-19.

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Characterization of renin-angiotensin system enzyme activities in cultured mouse podocytes

AJP Renal Physiology ◽

10.1152/ajprenal.00050.2007 ◽

2007 ◽

Vol 293 (1) ◽

pp. F398-F407 ◽

Cited By ~ 63

Author(s):

Juan Carlos Q. Velez ◽

Alison M. Bland ◽

John M. Arthur ◽

John R. Raymond ◽

Michael G. Janech

Keyword(s):

Mesangial Cells ◽

Renin Angiotensin System ◽

Ang Ii ◽

Glomerular Injury ◽

Renin Substrate ◽

Angiotensin System ◽

Renin Angiotensin ◽

Neprilysin Inhibitor ◽

Aminopeptidase A ◽

Aminopeptidase A Inhibitor

Intraglomerular ANG II has been linked to glomerular injury. However, little is known about the contribution of podocytes (POD) to intraglomerular ANG II homeostasis. The aim of the present study was to examine the processing of angiotensin substrates by cultured POD. Our approach was to use matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry for peptide determination from conditioned cell media and customized AQUA peptides for quantification. Immortalized mouse POD were incubated with 1-2 μM ANG I, ANG II, or the renin substrate ANG-(1-14) for different time intervals and coincubated in parallel with various inhibitors. Human mesangial cells (MES) were used as controls. POD incubated with 1 μM ANG I primarily formed ANG-(1-9) and ANG-(1-7). In contrast, MES incubated with ANG I primarily generated ANG II. In POD, ANG-(1-7) was the predominant product, and its formation was inhibited by a neprilysin inhibitor. Modest angiotensin-converting enzyme (ACE) activity was also detected in POD, although only after cells were incubated with 2 μM ANG I. In addition, we observed that POD degraded ANG II into ANG III and ANG-(1-7). An aminopeptidase A inhibitor inhibited ANG III formation, and an ACE2 inhibitor led to ANG II accumulation. Furthermore, we found that POD converted ANG-(1-14) to ANG I and ANG-(1-7). This conversion was inhibited by a renin inhibitor. These findings demonstrate that POD express a functional intrinsic renin-angiotensin system characterized by neprilysin, aminopeptidase A, ACE2, and renin activities, which predominantly lead to ANG-(1-7) and ANG-(1-9) formation, as well as ANG II degradation. These findings may reflect a specific role of POD in maintenance of intraglomerular renin-angiotensin system balance.

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Abstract 185: Transient Neonatal High Oxygen Exposure Leads to Cardiac Dysfunction and Renin Angiotensin System Activation in Rats

Hypertension ◽

10.1161/hyp.62.suppl_1.a185 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Mariane Bertagnolli ◽

Fanny Huyard ◽

Anik Cloutier ◽

Megan Sutherland ◽

Marie-Amélie Lukaszewski ◽

...

Keyword(s):

Cardiac Dysfunction ◽

Heart Development ◽

Heart Function ◽

Renin Angiotensin System ◽

Left Ventricular ◽

High Oxygen ◽

Angiotensin System ◽

Renin Angiotensin ◽

Ras Activation ◽

High O2

Preterm infants are exposed to high oxygen (O2) pressure (relative to intrauterine levels) leading to systemic oxidative stress and impaired vascular development; as children and adults, preterm born subjects have higher blood pressure. In rats, high O2 exposure induces vascular dysfunction, in part mediated by the renin angiotensin system (RAS). However, impact of neonatal high O2 exposure on heart development and whether RAS activation prevails in the heart is unknown. We aimed to assess early heart alterations and activation of RAS after neonatal high O2 exposure. METHODS AND RESULTS: Sprague-Dawley pups were kept with their mother in 80% O2 (O2, n=8) or room air (Ctrl, n=8) from days 3-10 of life. Hearts were extracted at day 3 (pre O2-exposure, P3), day 5 (during, P5), 10 (after, P10) and 4 wks to assess myocardium hypertrophy (HE), fibrosis (Masson’s trichrome) and RAS components gene expressions by RT-PCR. Echocardiography was performed at 4 weeks to assess heart function. RAS components mRNA expression in O2 vs Ctrls shows up-regulation of AT1a and ACE2 genes at P5 (AT1a: 152±28 vs 58±16/ACE2: 140±20 vs 77±6% of P3) and P10 (AT1a: 374±35 vs 250±30 /ACE2: 326±70 vs 208±18% of P3) relative to values at P3. With age, AT1b and AT2 expressions decrease in Ctrls, whereas are maintained in O2-exposed rats to values similar to P3 (Ctrl vs O2, P5: AT1b: 18±5 vs 71±12/AT2: 48±20 vs 120±16; P10: AT1b: 33±9 vs 105±26/AT2: 27±8 vs 77±7% of P3). At P10, cardiomyocyte surface area is increased in O2 vs Ctrls (4.9±0.2 vs 2.9±0.1 μm2). At 4 wks, O2 group show increased fibrosis (49±4 vs 29±2 % pixels), left ventricular (LV) cavity diameter (3.6±0.2 vs 3.0±0.1 mm) and systolic dysfunction by decreased fraction of shortening (39±2 vs 47±2 %). AT1b gene expression (2.6±1.7 vs 0.3±0.2) is increased and AT2 receptor (7.5±0.9 vs 6.0±0.6) is decreased in O2 group vs Ctrl. CONCLUSION: Neonatal O2 exposure activates RAS in hearts. AT1 receptor is up-regulated at all ages studied in O2-exposed rat hearts while AT2 is up-regulated at P5 and P10. At 4 wks, AT1/AT2 imbalance prevails in O2 group hearts along with LV dysfunction and enhanced fibrosis and hypertrophy. RAS activation by neonatal O2-exposure might significantly impact in heart development and programming of cardiac dysfunction in rats.

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