A2B Adenosine Receptor–Mediated Induction of IL-6 Promotes CKD

Dai, Yingbo; Zhang, Weiru; Wen, Jiaming; Zhang, Yujin; Kellems, Rodney E.; Xia, Yang

doi:10.1681/asn.2010080890

Cited by 90 publications

(103 citation statements)

References 45 publications

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“…32 In addition, the progression of renal fibrosis generated in the ADA À / À animals or in mice infused with angiotensin II (Ang II)or subjected to unilateral ureteral obstruction can be blocked using an A 2B AR antagonist, suggesting a common pathogenic pathway involving adenosine signaling in chronic kidney disease. 32 Our major contribution is to demonstrate that this pathogenic pathway also occurs early in the progression of the renal disease derived from diabetes thus supporting the option of a DN pharmacological A 2B AR target intervention.…”

Section: Discussionmentioning

confidence: 99%

Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

Cárdenas

Toledo

Oyarzún

et al. 2013

Laboratory Investigation

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Diabetic nephropathy ranks as the most devastating kidney disease worldwide. It characterizes in the early onset by glomerular hypertrophy, hyperfiltration and mesangial expansion. Experimental models show that overproduction of vascular endothelial growth factor (VEGF) is a pathogenic condition for podocytopathy; however the mechanisms that regulate this growth factor induction are not clearly identified. We determined that the adenosine A 2B receptor (A 2B AR) mediates VEGF overproduction in ex vivo glomeruli exposed to high glucose concentration, requiring PKCa and Erk1/2 activation. The glomerular content of A 2B AR was concomitantly increased with VEGF at early stages of renal disease in streptozotocin-induced diabetic rats. Further, in vivo administration of an antagonist of A 2B AR in diabetic rats blocked the glomerular overexpression of VEGF, mesangial cells activation and proteinuria. In addition, we also determined that the accumulation of extracellular adenosine occurs in glomeruli of diabetic rats. Correspondingly, raised urinary adenosine levels were found in diabetic rats. In conclusion, we evidenced that adenosine signaling at the onset of diabetic kidney disease is a pathogenic event that promotes VEGF induction.

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Section: Discussionmentioning

confidence: 99%

Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

Cárdenas

Toledo

Oyarzún

et al. 2013

Laboratory Investigation

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“…A 2A R KO mice develop increased renal fibrosis and increased inflammatory cell infiltrate compared to WT mice on days 3 and 7 of UUO; however, by day 14, the extent of fibrosis was comparable in both groups [9]. Dai et al demonstrated that A 2B R KO mice developed less renal fibrosis after 14 days of UUO compared to WT mice, indicating a pro-fibrotic role of the A 2B R in the UUO model [11]. These data suggest that the A 2A R may modulate the early stages of UUO, whereas the A 2B R plays a more significant role in the latter stages of fibrosis.…”

Section: Introductionmentioning

confidence: 99%

“…In mice deficient of the enzyme adenosine deaminase (ADA), which converts adenosine to inosine, high levels of renal adenosine content lead to increased renal fibrosis via the A 2B R [11]. In a model of angiotensin IIinduced hypertension, renal fibrosis develops through increased activity of CD73 and adenosine generation.…”

Section: Introductionmentioning

confidence: 99%

CD39 overexpression does not attenuate renal fibrosis in the unilateral ureteric obstructive model of chronic kidney disease

Roberts

Lü

Chia

et al. 2016

Purinergic Signalling

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Chronic kidney disease has multiple etiologies, but its single, hallmark lesion is renal fibrosis. CD39 is a key purinergic enzyme in the hydrolysis of ATP and increased CD39 activity on regulatory T cells (Treg) is protective in adriamycin-induced renal fibrosis. We examined the effect of overexpression of human CD39 on the development of renal fibrosis in the unilateral ureteric obstructive (UUO) model, a model widely used to study the molecular and cellular factors involved in renal fibrosis. Mice overexpressing human CD39 (CD39Tg) and their wild-type (WT) littermates were subjected to UUO; renal histology and messenger RNA (mRNA) levels of adenosine receptors and markers of renal fibrosis were examined up to 14 days after UUO. There were no differences between CD39Tg mice and WT mice in the development of renal fibrosis at days 3, 7, and 14 of UUO. Relative mRNA expression of the adenosine A 2A receptor and endothelin-1 were higher in CD39Tg than WT mice at day 7 post UUO, but there were no differences in markers of fibrosis. We conclude that human CD39 overexpression does not attenuate the development of renal fibrosis in the UUO model. The lack of protection by CD39 overexpression in the UUO model is multifactorial due to the different effects of adenosinergic receptors on the development of renal fibrosis.

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“…For example, the uncontrolled accumulation of adenosine in ADA-deficient mice leads to widespread activation of adenosine receptors with detrimental effects in many areas of pathology including pulmonary inflammatory damage, 20,48,49 priapism, 50,51 and chronic kidney injury. 37 Our study here using ADAdeficient mice and PEG-ADA enzyme therapy provides genetic evidence indicating the important and previously unknown function of excess adenosine signaling in regulating erythrocyte SphK1 activity. PEG-ADA enzyme therapy has been used to treat ADA-deficient humans for .30 years.…”

Section: Discussionmentioning

confidence: 71%

“…The Gs-coupled ADORA2B signaling involves many downstream components including PKA 37 and ERK1/2. 38 Previous study showed the involvement of PKA in adenosine-ADORA2B-mediated induction of 2,3-bisphosphoglycerate in erythrocytes.…”

Section: Blood 5 March 2015 X Volume 125 Number 10 Regulation Of Nomentioning

confidence: 99%

Elevated adenosine signaling via adenosine A2B receptor induces normal and sickle erythrocyte sphingosine kinase 1 activity

Sun¹,

Zhang²,

Bogdanov³

et al. 2015

Blood

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• Adenosine signaling via ADORA2B induces SphK1 activity in sickle and normal erythrocytes via PKA-mediated ERK1/2 activation.• Lowering adenosine by PEG-ADA or interfering ADORA2B activation by specific antagonist decreases SphK1 activity in normal and sickle RBCs.Erythrocyte possesses high sphingosine kinase 1 (SphK1) activity and is the major cell type supplying plasma sphingosine-1-phosphate, a signaling lipid regulating multiple physiological and pathological functions. Recent studies revealed that erythrocyte SphK1 activity is upregulated in sickle cell disease (SCD) and contributes to sickling and disease progression. However, how erythrocyte SphK1 activity is regulated remains unknown. Here we report that adenosine induces SphK1 activity in human and mouse sickle and normal erythrocytes in vitro. Next, using 4 adenosine receptor-deficient mice and pharmacological approaches, we determined that the A2B adenosine receptor (ADORA2B) is essential for adenosine-induced SphK1 activity in human and mouse normal and sickle erythrocytes in vitro. Subsequently, we provide in vivo genetic evidence that adenosine deaminase (ADA) deficiency leads to excess plasma adenosine and elevated erythrocyte SphK1 activity. Lowering adenosine by ADA enzyme therapy or genetic deletion of ADORA2B significantly reduced excess adenosine-induced erythrocyte SphK1 activity in ADA-deficient mice. Finally, we revealed that protein kinase A-mediated extracellular signal-regulated kinase 1/2 activation functioning downstream of ADORA2B underlies adenosine-induced erythrocyte SphK1 activity. Overall, our findings reveal a novel signaling network regulating erythrocyte SphK1 and highlight innovative mechanisms regulating SphK1 activity in normal and SCD. (Blood. 2015; 125(10):1643-1652

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A2B Adenosine Receptor–Mediated Induction of IL-6 Promotes CKD

Cited by 90 publications

References 45 publications

Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

CD39 overexpression does not attenuate renal fibrosis in the unilateral ureteric obstructive model of chronic kidney disease

Elevated adenosine signaling via adenosine A2B receptor induces normal and sickle erythrocyte sphingosine kinase 1 activity

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