scholarly journals Angiotensin II down-regulates nephrin–Akt signaling and induces podocyte injury: role of c-Abl

2016 ◽  
Vol 27 (1) ◽  
pp. 197-208 ◽  
Author(s):  
Qian Yang ◽  
Yiqiong Ma ◽  
Yipeng Liu ◽  
Wei Liang ◽  
Xinghua Chen ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Vital Role ◽  
Sh2 Domain ◽  
Renal Diseases ◽  
Ang Ii ◽  
Podocyte Injury ◽  
Nonreceptor Tyrosine Kinase ◽  
Inositol Phosphatase ◽  
Interfering Rna

Recent studies have shown that nephrin plays a vital role in angiotensin II (Ang II)–induced podocyte injury and thus contributes to the onset of proteinuria and the progression of renal diseases, but its specific mechanism remains unclear. c-Abl is an SH2/SH3 domain–containing nonreceptor tyrosine kinase that is involved in cell survival and regulation of the cytoskeleton. Phosphorylated nephrin is able to interact with molecules containing SH2/SH3 domains, suggesting that c-Abl may be a downstream molecule of nephrin signaling. Here we report that Ang II–infused rats developed proteinuria and podocyte damage accompanied by nephrin dephosphorylation and minimal interaction between nephrin and c-Abl. In vitro, Ang II induced podocyte injury and nephrin and Akt dephosphorylation, which occurred in tandem with minimal interaction between nephrin and c-Abl. Moreover, Ang II promoted c-Abl phosphorylation and interaction between c-Abl and SH2 domain–containing 5′-inositol phosphatase 2 (SHIP2). c-Abl small interfering RNA (siRNA) and STI571 (c-Abl inhibitor) provided protection against Ang II–induced podocyte injury, suppressed the Ang II-induced c-Abl–SHIP2 interaction and SHIP2 phosphorylation, and maintained a stable level of nephrin phosphorylation. These results indicate that c-Abl is a molecular chaperone of nephrin signaling and the SHIP2-Akt pathway and that the released c-Abl contributes to Ang II–induced podocyte injury.

scholarly journals Dab1 Contributes to Angiotensin II-Induced Apoptosis via p38 Signaling Pathway in Podocytes

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Zhao Gao ◽  
Xinghua Chen ◽  
Kai Zhu ◽  
Ping Zeng ◽  
Guohua Ding
Keyword(s):  
Angiotensin Ii ◽  
Signaling Pathway ◽  
Underlying Mechanism ◽  
Vital Role ◽  
Protective Effects ◽  
Ang Ii ◽  
Induced Apoptosis ◽  
End Stage ◽  
Interfering Rna

Numerous studies have found that angiotensin II (Ang II) participates in podocyte apoptosis and exacerbates progression of end-stage kidney disease (ESKD). However, its underlying mechanism remains largely unexplored. As a homolog of Drosophila disabled (Dab) protein, Dab1 plays a vital role in cytoskeleton, neuronal migration, and proliferation. In the present study, our data revealed that Ang II-infused rats developed hypertension, proteinuria, and podocyte injury accompanied by Dab1 phosphorylation and increased reelin expression in kidney. Moreover, Ang II induced podocyte apoptosis in vitro. Dab1 phosphorylation and reelin expression in podocytes were increased after exposure to Ang II. Conversely, Dab1 small interfering RNA (siRNA) exerted protective effects on Ang II-induced podocyte apoptosis, resulting in decreased p38 phosphorylation and reelin expression. These results indicated that Dab1 mediated Ang II-induced podocyte apoptosis via p38 signaling pathway.

scholarly journals Rapamycin Attenuated Podocyte Apoptosis Via Upregulation of Nestin in Ang II-Induced Podocyte Injury

2021 ◽  
Author(s):  
Huimin Shi ◽  
Yajie Zhao ◽  
Tiantian He ◽  
Xianli Wen ◽  
Gaoting Qu ◽  
...  
Keyword(s):  
Animal Model ◽  
Angiotensin Ii ◽  
Mtor Inhibitor ◽  
Convincing Evidence ◽  
Ang Ii ◽  
Podocyte Injury ◽  
Protection Effect ◽  
Cytoskeleton Protein

Abstract Background: Angiotensin II (Ang II) contributes to the progression of glomerulosclerosis mainly by inducing podocyte injury. Convincing evidence indicates that the mTOR inhibitor rapamycin plays a fundamental role in the protection of podocyte injury. Nestin, a major cytoskeleton protein, is expressed stably in podocytes and correlates with podocyte damage. The purpose of this study was to investigate the effect of rapamycin in podocyte injury induced by Ang II, and clarify the role and mechanism of Nestin in the protection of podocyte injury.Methods and Results: We established an Ang II perfusion animal model, and the effects of interfere treatment of rapamycin on podocyte were detected in vivo. In vitro, podocytes were stimulated with Ang II and rapamycin to observe podocyte injury, nestin-siRNA was transfected to investigate the mechanism in the process. We observed that Ang II induce podocyte injury both in vivo and in vitro, while rapamycin treatment relieved Ang II-induced podocyte injury. Also we found that nestin co-localized with p-mTOR in glomeruli, and the protection effect of rapamycin was reduced by nestin-siRNA in podocytes. Moreover, co-IP indicated the interaction between nestin and p-mTOR, and nestin could affect podocyte injury via mTOR/P70S6K signaling pathway.Conlusion: Thus, here, we demonstrated that Rapamycin attenuated podocyte apoptosis via upregulation of nestin through mTOR/P70S6K signsling pathway in Ang II-induced podocyte injury.

Interrenal activity in the female lizard Lagerta vivipara J.: In vitro response to ACTH 1–39 and to [SAR1, VAL5] angiotensin II (ANG II)

1988 ◽  
Vol 30 (1-6) ◽  
pp. 457-460 ◽  
Author(s):  
Chantal Dauphin-Villemant ◽  
François Leboulenger ◽  
Françoise Xavier ◽  
Hubert Vaudry
Keyword(s):  
Angiotensin Ii ◽  
Ang Ii ◽  
In Vitro Response ◽  
Female Lizard

Vasoconstriction of outer medullary vasa recta by angiotensin II is modulated by prostaglandin E2

1994 ◽  
Vol 266 (6) ◽  
pp. F850-F857 ◽  
Author(s):  
T. L. Pallone
Keyword(s):  
Angiotensin Ii ◽  
Prostaglandin E2 ◽  
Regional Blood Flow ◽  
Renal Medulla ◽  
Hydraulic Pressure ◽  
Vascular Bundles ◽  
Ang Ii ◽  
Vasa Recta ◽  
Anatomical Arrangement

Vasa recta were dissected from outer medullary vascular bundles in the rat and perfused in vitro. Examination by transmission electron microscopy reveals them to be only outer medullary descending vasa recta (OM-DVR). To establish a method for systematic examination of vasoconstriction, OMDVR were perfused at 5 nl/min with collection pressure increased to 5 mmHg. Under these conditions, transmembrane volume flux was found to be near zero, and the transmural hydraulic pressure gradient was found to be < 15 mmHg. Over a concentration range of 10(-12) to 10(-8) M, abluminal application of angiotensin II (ANG II) caused graded focal vasoconstriction of OMDVR that is blocked by saralasin. Luminal application of ANG II over the same concentration range was much less effective. Abluminal application of prostaglandin E2 (PGE2) shifted the vasoconstrictor response of OMDVR to higher ANG II concentrations. PGE2 reversibly dilated OMDVR that had been preconstricted by ANG II. These results demonstrate that OMDVR are vasoactive segments. Their anatomical arrangement suggests that they play a key role in the regulation of total and regional blood flow to the renal medulla.

Systemic administration of naked plasmid encoding HGF attenuates puromycin aminonucleoside-induced damage of murine glomerular podocytes

2011 ◽  
Vol 301 (4) ◽  
pp. F784-F792 ◽  
Author(s):  
Xuan Bu ◽  
Yang Zhou ◽  
Hua Zhang ◽  
Wenjing Qiu ◽  
Lu Chen ◽  
...  
Keyword(s):  
Wilms Tumor ◽  
Gene Transfection ◽  
Systemic Administration ◽  
Renal Diseases ◽  
Puromycin Aminonucleoside ◽  
Podocyte Injury ◽  
Rapid Injection ◽  
Naked Plasmid

Podocyte injury is considered to play important roles in the pathogenesis of human glomerular disease. There is accumulating evidence suggesting that hepatocyte growth factor (HGF) elicits preventive activity for glomerular cells in animal models of chronic renal diseases. In this study, we demonstrated that delivery of a naked plasmid vector encoding the human HGF gene into mice by a hydrodynamic-based in vivo gene transfection approach markedly reduced proteinuria and attenuated podocyte injury in a mouse model induced by puromycin aminonucleoside (PAN) injection. Systemic administration by rapid injection via the tail vein of a naked plasmid containing HGF cDNA driven under a cytomegalovirus promoter (pCMV-HGF) produced a remarkable level of human HGF protein in the circulation. Tissue distribution studies suggested that the kidney expressed a high level of the HGF transgene. Meanwhile, compared with tubules and interstitium, a higher level of exogenous HGF protein was detected in the glomeruli. Administration of pCMV-HGF dramatically abated the urine albumin excretion and podocyte injury in PAN nephropathy in mice. Exogenous expression of HGF produced evidently beneficial effects, leading to restoration of Wilms' tumor-1 (WT1) and α-actinin-4 expression and attenuation of ultrastructural damage of the podocytes. In vitro, HGF not only restored WT1 and α-actinin-4 expression but also inhibited albumin leakage of podocytes incubated with PAN in a Transwell culture chamber. These results suggest that HGF might provide a novel strategy for amelioration of podocyte injury.

Angiotensin II modulates frizzled-2 receptor expression in rat vascular smooth muscle cells

2005 ◽  
Vol 108 (6) ◽  
pp. 523-530 ◽  
Author(s):  
Giovanna CASTOLDI ◽  
Serena REDAELLI ◽  
Willy M. M. van de GREEF ◽  
Cira R. T. di GIOIA ◽  
Giuseppe BUSCA ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Ang Ii ◽  
Aortic Smooth Muscle

Ang II (angiotensin II) has multiple effects on vascular smooth muscle cells through the modulation of different classes of genes. Using the mRNA differential-display method to investigate gene expression in rat aortic smooth muscle cells in culture in response to 3 h of Ang II stimulation, we observed that Ang II down-regulated the expression of a member of the family of transmembrane receptors for Wnt proteins that was identified as Fzd2 [Fzd (frizzled)-2 receptor]. Fzds are a class of highly conserved genes playing a fundamental role in the developmental processes. In vitro, time course experiments demonstrated that Ang II induced a significant increase (P<0.05) in Fzd2 expression after 30 min, whereas it caused a significant decrease (P<0.05) in Fzd2 expression at 3 h. A similar rapid up-regulation after Ang II stimulation for 30 min was evident for TGFβ1 (transforming growth factor β1; P<0.05). To investigate whether Ang II also modulated Fzd2 expression in vivo, exogenous Ang II was administered to Sprague–Dawley rats (200 ng·kg−1 of body weight·min−1; subcutaneously) for 1 and 4 weeks. Control rats received normal saline. After treatment, systolic blood pressure was significantly higher (P<0.01), whereas plasma renin activity was suppressed (P<0.01) in Ang II- compared with the saline-treated rats. Ang II administration for 1 week did not modify Fzd2 expression in aorta of Ang II-treated rats, whereas Ang II administration for 4 weeks increased Fzd2 mRNA expression (P<0.05) in the tunica media of the aorta, resulting in a positive immunostaining for fibronectin at this time point. In conclusion, our data demonstrate that Ang II modulates Fzd2 expression in aortic smooth muscle cells both in vitro and in vivo.

Capn4 aggravates angiotensin II-induced cardiac hypertrophy by activating the IGF-AKT signaling pathway

2021 ◽  
Author(s):  
Yuanping Cao ◽  
Qun Wang ◽  
Caiyun Liu ◽  
Wenjun Wang ◽  
Songqing Lai ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Signaling Pathway ◽  
Expression Patterns ◽  
Akt Signaling ◽  
Calpain Inhibitor ◽  
Ang Ii ◽  
Akt Signaling Pathway ◽  
Calpain Activity

Abstract Capn4 belongs to a family of calpains that participate in a wide variety of biological functions, but little is known about the role of Capn4 in cardiac disease. Here, we show that the expression of Capn4 was significantly increased in Angiotensin II (Ang II)-treated cardiomyocytes and Ang II-induced cardiac hypertrophic mouse hearts. Importantly, in agreement with the Capn4 expression patterns, the maximal calpain activity measured in heart homogenates was elevated in Ang II-treated mice, and oral coadministration of SNJ-1945 (calpain inhibitor) attenuated the total calpain activity measured in vitro. Functional assays indicated that overexpression of Capn4 obviously aggravated Ang II-induced cardiac hypertrophy, whereas Capn4 knockdown resulted in the opposite phenotypes. Further investigation demonstrated that Capn4 maintained the activation of the insulin-like growth factor (IGF)-AKT signaling pathway in cardiomyocytes by increasing c-Jun expression. Mechanistic investigations revealed that Capn4 directly bound and stabilized c-Jun, and knockdown of Capn4 increased the ubiquitination level of c-Jun in cardiomyocytes. Additionally, our results demonstrated that the antihypertrophic effect of Capn4 silencing was partially dependent on the inhibition of c-Jun. Overall, these data suggested that Capn4 contributes to cardiac hypertrophy by enhancing the c-Jun-mediated IGF-AKT signaling pathway and could be a potential therapeutic target for hypertrophic cardiomyopathy.

Abstract MP03: ROCK2 Specific Inhibition Attenuates Angiotensin II-induced Hypertension In Mice

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Daniel J Fehrenbach ◽  
Meena S Madhur
Keyword(s):  
Blood Pressure ◽  
T Cell ◽  
Angiotensin Ii ◽  
Repeated Measures ◽  
Flow Cytometric Analysis ◽  
Coiled Coil ◽  
Ang Ii ◽  
Induced Hypertension

Hypertension, or an elevated blood pressure, is the primary modifiable risk factor for cardiovascular disease, the number one cause of mortality worldwide. We previously demonstrated that Th17 activation and interleukin 17A (IL-17A)/IL-21 production is integral for the full development of a hypertensive phenotype as well as the renal and vascular damage associated with hypertension. Rho-associated coiled-coil containing protein Kinase 2 (ROCK2) serves as a molecular switch upregulating Th17 and inhibiting regulatory T cell (Treg) differentiation. We hypothesize that hypertension is characterized by excessive T cell ROCK2 activation leading to increased Th17/Treg ratios and ultimately end-organ damage. We first showed in vitro that KD025, an experimental orally bioavailable ROCK2 inhibitor inhibits Th17 cell proliferation and IL-17A/IL-21 production. To determine if hypertensive stimuli such as endothelial stretch increases T cell ROCK2 expression, we cultured human aortic endothelial cells exposed to 5% (normotensive) or 10% (hypertensive) stretch with circulating human T cells and HLA-DR+ antigen presenting cells. Hypertensive stretch increased T cell ROCK2 expression 2-fold. We then tested the effect of ROCK2 inhibition with KD025 (50mg/kg i.p. daily) in vivo on angiotensin II (Ang II)-induced hypertension. Treatment with KD025 significantly attenuated the hypertensive response within 1 week of Ang II treatment (systolic blood pressure: 139± 8 vs 108±7mmHg) and this persisted for the duration of the 4 week study reaching blood pressures 20 mmHg lower (135±13mmHg) than vehicle treated mice (158±4mmHg p<0.05 effect of treatment 2-way Repeated Measures ANOVA). Flow cytometric analysis of tissue infiltrating leukocytes revealed that KD025 treatment increased Treg/Th17 ratios in the kidney (0.61±0.03 vs 0.79±0.08, p<0.05 student’s t-test). Thus, T cell ROCK2 may be a novel therapeutic target for the treatment of hypertension.

Membrane potential measurements in renal afferent and efferent arterioles: actions of angiotensin II

1997 ◽  
Vol 273 (2) ◽  
pp. F307-F314 ◽  
Author(s):  
R. Loutzenhiser ◽  
L. Chilton ◽  
G. Trottier
Keyword(s):  
Angiotensin Ii ◽  
Perfusion Pressure ◽  
Rat Kidney ◽  
Renal Perfusion ◽  
Membrane Potentials ◽  
Ang Ii ◽  
Ca Channels ◽  
Renal Perfusion Pressure

An adaptation of the in vitro perfused hydronephrotic rat kidney model allowing in situ measurement of arteriolar membrane potentials is described. At a renal perfusion pressure of 80 mmHg, resting membrane potentials of interlobular arteries (22 +/- 2 microns) and afferent (14 +/- 1 microns) and efferent arterioles (12 +/- 1 microns) were -40 +/- 2 (n = 8), -40 +/- 1 (n = 45), and -38 +/- 2 mV (n = 22), respectively (P = 0.75). Using a dual-pipette system to stabilize the impalement site, we measured afferent and efferent arteriolar membrane potentials during angiotensin II (ANG II)-induced vasoconstriction. ANG II (0.1 nM) reduced afferent arteriolar diameters from 13 +/- 1 to 8 +/- 1 microns (n = 8, P = 0.005) and membrane potentials from -40 +/- 2 to -29 +/- mV (P = 0.012). ANG II elicited a similar vasoconstriction in efferent arterioles, decreasing diameters from 13 +/- 1 to 8 +/- 1 microns (n = 8, P = 0.004), but failed to elicit a significant depolarization (-39 +/- 2 for control; -36 +/- 3 mV for ANG II; P = 0.27). Our findings thus indicate that resting membrane potentials of pre- and postglomerular arterioles are similar and lie near the threshold activation potential for L-type Ca channels. ANG II-induced vasoconstriction appears to be closely coupled to membrane depolarization in the afferent arteriole, whereas mechanical and electrical responses appear to be dissociated in the efferent arteriole.

Angiotensin II effects on microvascular diameters of in vitro blood-perfused juxtamedullary nephrons

1986 ◽  
Vol 251 (4) ◽  
pp. F610-F618 ◽  
Author(s):  
P. K. Carmines ◽  
T. K. Morrison ◽  
L. G. Navar
Keyword(s):  
Angiotensin Ii ◽  
Constant Pressure ◽  
Ang Ii ◽  
Experimental Conditions ◽  
Vasoactive Hormones ◽  
Juxtamedullary Nephron ◽  
Single Nephron ◽  
Afferent Arterioles ◽  
Dose Dependent

The purpose of this study was to determine the specific renal microvascular segments that are functionally responsive to angiotensin II (ANG II) and other vasoactive hormones. Experiments were performed on juxtamedullary tissue from captopril-treated rats during perfusion with blood at a constant pressure of 110 mmHg. Epifluorescence videomicroscopy was utilized to measure diameters of arcuate and interlobular arteries (ART), mid- (MA) and late- (LA) afferent arterioles, and efferent arterioles (EA). Norepinephrine (700 nM) significantly decreased, and sodium nitroprusside (380 nM) increased, inside diameters of all segments. Topical application of ANG II (0.01 to 1 nM) induced significant reductions in diameters of all vessel segments: ART, 17.5 +/- 2.0%; MA, 19.6 +/- 2.5%; LA, 13.5 +/- 1.5%; and EA, 16.9 +/- 2.7%. The preglomerular response to ANG II was blocked by saralasin (10 microM) and, in most cases, was dose dependent; however, an initial hypersensitivity to low ANG II doses (30% decrease in diameter) was exhibited by 38% of the preglomerular vessels studied. Under these experimental conditions, single-nephron glomerular filtration rate decreased significantly in response to 0.01 nM ANG II exposure. These observations demonstrate that physiological concentrations of ANG II can elicit receptor-dependent and reversible vasoconstriction of the juxtamedullary nephron microvasculature at both pre- and postglomerular sites.

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