Adenosine Restores Angiotensin II–Induced Contractions by Receptor-Independent Enhancement of Calcium Sensitivity in Renal Arterioles

Lai, En Yin; Martinka, Peter; Fähling, Michael; Mrowka, Ralf; Steege, Andreas; Gericke, Adrian; Sendeski, Mauricio; Persson, Pontus B.; Persson, A. Erik G.; Patzak, Andreas

doi:10.1161/01.res.0000249530.85542.d4

Cited by 48 publications

(75 citation statements)

References 44 publications

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“…Accordingly, we propose that adenosine exerts its effects independently of the known receptors. Since the adenosine transporter enhances the intracellular adenosine level and restores the constriction ability in renal endothelial cells (Lai et al, 2006), we examined the possible involvement of adenosine transporters in adenosine-induced HO-1 expression. However, in our studies, adenosine transporter inhibitors, S-(4-nitrobenzyl)-6-thioinosine (NBTI) and dipyridamole, had no effect on HO-1 expression (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

Min

Kim

Jou

et al. 2008

Glia

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Adenosine, a purine nucleoside, has been reported to suppress the inflammatory responses of microglia in the brain. However, the underlying mechanisms of its anti-inflammatory action are unclear at present. Here we show that adenosine reduces the increase in intracellular reactive oxygen species (ROS) through expression of an antioxidant enzyme, hemeoxygenase-1 (HO-1). The H 2 O 2 -induced intracellular ROS level was significantly low in microglia pretreated with adenosine for 3-6 h, compared with that in untreated cells. Adenosine induced HO-1 mRNA and protein expression within 3 h, which was maintained for up to 12 h. Nuclear factor E2-related factor 2 (Nrf2), a transcription factor, and phosphatidylinositol 3-kinase (PI3K) and Akt pathways appear to mediate HO-1 expression. In response to adenosine, Nrf2 translocated from the cytosol to nuclei, and bound to the antioxidant response element (ARE). Adenosine enhanced HO-1 promoter activity in an ARE-dependent manner. Moreover, the nucleoside stimulated Akt phosphorylation, and suppressors of PI3K (LY294002 and wortmannin) reduced adenosine-induced HO-1 expression. However, we propose that the effects of adenosine are independent of adenosine receptors, since agonists and antagonists of A1, A2a, and A3 had little effect on the regulation of intracellular ROS and HO-1 expression. Our results collectively suggest that adenosine acts as an endogenous regulator of brain inflammation via modulation of microglial ROS production. V

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Section: Discussionmentioning

confidence: 99%

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

Min

Kim

Jou

et al. 2008

Glia

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“…5,6 Adenosine and Ang II interact on AAs via calcium-dependent and calcium-independent pathways. 25,35 Low concentrations of adenosine increase the response of afferent AA to Ang II via predominant action on A 1 receptors. 23 In the present study, even high concentrations of adenosine, also activating dilatory A 2 receptors, increased the Ang II response in the hydronephrotic kidney.…”

Section: Discussionmentioning

confidence: 99%

“…Preglomerular vessels (including mainly interlobular arteries and AAs) of mice were isolated with a modified iron oxide-sieving technique described previously 24,25 and immediately stored at Ϫ80°C.…”

Section: Isolation Of Preglomerular Vesselsmentioning

confidence: 99%

Nitric Oxide Deficiency and Increased Adenosine Response of Afferent Arterioles in Hydronephrotic Mice With Hypertension

et al. 2008

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Abstract-Afferent arterioles were used to investigate the role of adenosine, angiotensin II, NO, and reactive oxygen species in the pathogenesis of increased tubuloglomerular feedback response in hydronephrosis. Hydronephrosis was induced in wild-type mice, superoxide dismutase-1 overexpressed mice (superoxide-dismutase-1 transgenic), and deficient mice (superoxide dismutase-1 knockout). Isotonic contractions in isolated perfused arterioles and mRNA expression of NO synthase isoforms, adenosine, and angiotensin II receptors were measured. In wild-type mice, N G -nitro-L-arginine methyl ester (L-NAME) did not change the basal arteriolar diameter of hydronephrotic kidneys (Ϫ6%) but reduced it in control (Ϫ12%) and contralateral arterioles (Ϫ43%). Angiotensin II mediated a weaker maximum contraction of hydronephrotic arterioles (Ϫ18%) than in control (Ϫ42%) and contralateral arterioles (Ϫ49%). The maximum adenosine-induced constriction was stronger in hydronephrotic (Ϫ19%) compared with control (Ϫ8%) and contralateral kidneys (Ϯ0%). The response to angiotensin II became stronger in the presence of adenosine in hydronephrotic kidneys and attenuated in contralateral arterioles. L-NAME increased angiotensin II responses of all of the groups but less in hydronephrotic kidneys. The mRNA expression of endothelial NO synthase and inducible NO synthase was upregulated in the hydronephrotic arterioles. No differences were found for adenosine or angiotensin II receptors. In superoxide dismutase-1 transgenic mice, strong but similar L-NAME response (Ϫ40%) was observed for all of the groups. This response was totally abolished in arterioles of hydronephrotic superoxide dismutase-1 knockout mice. In conclusion, hydronephrosis is associated with changes in the arteriolar reactivity of both hydronephrotic and contralateral kidneys. Increased oxidative stress, reduced NO availability, and stronger reactivity to adenosine of the hydronephrotic kidney may contribute to the enhanced tubuloglomerular feedback responsiveness in hydronephrosis and be involved in the development of hypertension. Key Words: angiotensin II Ⅲ L-NAME Ⅲ oxidative stress Ⅲ NO synthase Ⅲ superoxide dismutase Ⅲ tubuloglomerular feedback H ydronephrosis because of uretero-pelvic junction obstruction is a common condition in newborns, with an incidence of Ϸ1%. Both rats and mice with hydronephrosis, because of chronic partial ureteral obstruction, develop renal injury 1 and salt-sensitive hypertension 2,3 that can be attenuated by relief of the obstruction. 4 The mechanisms are thought to be associated with increased activity of the renin-angiotensin system, 2 increased oxidative stress, and reduced NO availability in the diseased kidney. 5 In micropuncture studies of hydronephrotic animals, the tubuloglomerular feedback (TGF) has a higher responsiveness in the hydronephrotic kidney. 5,6 An increased TGF response, as seen in hydronephrotic kidneys, has also been described in spontaneously hypertensive rats, 7 Milan hypertensive rats 8 during development of hyperte...

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“…61 Proteins were separated by SDS-PAGE and transferred to Hybond-P membranes. Caspase-3 protein was detected using a specific antibody (#AM08377PU-N; Acris Antibodies GmbH, Herford, Germany) and secondary antibody goatanti-mouse (#sc2031, dilution 1:100,000; Santa Cruz Biotechnology, Santa Cruz, CA).…”

Section: Western Blot Analysesmentioning

confidence: 99%

Tubular von Hippel-Lindau Knockout Protects against Rhabdomyolysis-Induced AKI

Fähling¹,

Mathia

Paliege

et al. 2013

Journal of the American Society of Nephrology

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Renal hypoxia occurs in AKI of various etiologies, but adaptation to hypoxia, mediated by hypoxiainducible factor (HIF), is incomplete in these conditions. Preconditional HIF activation protects against renal ischemia-reperfusion injury, yet the mechanisms involved are largely unknown, and HIF-mediated renoprotection has not been examined in other causes of AKI. Here, we show that selective activation of HIF in renal tubules, through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO), protects from rhabdomyolysis-induced AKI. In this model, HIF activation correlated inversely with tubular injury. Specifically, VHL deletion attenuated the increased levels of serum creatinine/urea, caspase-3 protein, and tubular necrosis induced by rhabdomyolysis in wild-type mice. Moreover, HIF activation in nephron segments at risk for injury occurred only in VHL-KO animals. At day 1 after rhabdomyolysis, when tubular injury may be reversible, the HIF-mediated renoprotection in VHL-KO mice was associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal, as demonstrated by quantitative PCR, pathway enrichment analysis, and immunohistochemistry. In conclusion, a HIF-mediated shift toward improved energy supply may protect against acute tubular injury in various forms of AKI. 24: 180624: -181924: , 201324: . doi: 10.1681 No specific therapy is currently available for human AKI, a clinical entity of increasing incidence and high morbidity and mortality. 1-4 Rhabdomyolysis, one of the leading causes of AKI, develops after trauma, drug toxicity, infections, burns, and physical exertion. [5][6][7][8] The animal model using an intramuscular glycerol injection with consequent myoglobinuria is closely related to the human syndrome of rhabdomyolysis. 9 Experimental data demonstrate renal vasoconstriction, 9-15 tubular hypoxia, 15,16 normal or even reduced intratubular pressure, 9-11 as well as large variation in single nephron GFR. 10,11 Intratubular myoglobin casts, a histologic hallmark, seem not to cause tubular obstruction, 9-11 but rather scavenge nitric oxide 17,18 and generate reactive oxygen species 19 followed by vasoconstriction. J Am Soc NephrolThe traditional discrimination between ischemic and toxic forms of AKI has been challenged because an increasing amount of evidence suggests that renal hypoxia is a common denominator in AKI of different etiologies. 20 Pimonidazole adducts, which accumulate in tissues at oxygen tensions ,10 mmHg, 21 have been demonstrated in various AKI forms. 16,[22][23][24] During AKI, hypoxia-inducible factors (HIFs), which are mainly regulated by oxygen-dependent proteolysis, were found to be upregulated in different renal tubular segments. 16,20,22,24,25 HIFs are heterodimers of a constitutive b subunit, HIF-b (ARNT), and one of three oxygen-dependent a-subunits, HIF-1a, HIF-2a, and HIF-3a. The a-b dimers bind to hypoxia-response elements (HREs) in the promoter-enhancer region of HIF target genes. [26][27]...

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Adenosine Restores Angiotensin II–Induced Contractions by Receptor-Independent Enhancement of Calcium Sensitivity in Renal Arterioles

Cited by 48 publications

References 44 publications

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

Nitric Oxide Deficiency and Increased Adenosine Response of Afferent Arterioles in Hydronephrotic Mice With Hypertension

Tubular von Hippel-Lindau Knockout Protects against Rhabdomyolysis-Induced AKI

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