Elevated Ecto-5'-nucleotidase-Mediated Increased Renal Adenosine Signaling Via A2B Adenosine Receptor Contributes to Chronic Hypertension

Abstract

Rationale Hypertension is the most prevalent life-threatening disease worldwide and is frequently associated with chronic kidney disease (CKD). However, the molecular basis underlying hypertensive CKD is not fully understood. Objective We sought to identify specific factors and signaling pathways that contribute to hypertensive CKD and thereby exacerbate disease progression. Methods and Results Using high-throughput quantitative reverse-transcription polymerase chain reaction profiling, we discovered that the expression level of 5′-ectonucleotidase (CD73), a key enzyme that produces extracellular adenosine, was significantly increased in the kidneys of angiotensin II–infused mice, an animal model of hypertensive nephropathy. Genetic and pharmacological studies in mice revealed that elevated CD73-mediated excess renal adenosine preferentially induced A2B adenosine receptor (ADORA2B) production and that enhanced kidney ADORA2B signaling contributes to angiotensin II–induced hypertension. Similarly, in humans, we found that CD73 and ADORA2B levels were significantly elevated in the kidneys of CKD patients compared with normal individuals and were further elevated in hypertensive CKD patients. These findings led us to further discover that elevated renal CD73 contributes to excess adenosine signaling via ADORA2B activation that directly stimulates endothelin-1 production in a hypoxia-inducible factor-α–dependent manner and underlies the pathogenesis of the disease. Finally, we revealed that hypoxia-inducible factor-α is an important factor responsible for angiotensin II–induced CD73 and ADORA2B expression at the transcriptional level. Conclusions Overall, our studies reveal that angiotensin II–induced renal CD73 promotes the production of renal adenosine that is a prominent driver of hypertensive CKD by enhanced ADORA2B signaling–mediated endothelin-1 induction in a hypoxia-inducible factor-α–dependent manner. The inhibition of excess adenosine-mediated ADORA2B signaling represents a novel therapeutic target for the disease.

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

“…A 2B R activation promotes upregulation of ET-1 mRNA expression, similar to the A 2B R-mediated stimulation of ET-1 production described by Zhang et al in mice with angiotensin II-induced hypertension [12]. At day 7 post UUO, the expression of A 2A R was elevated in CD39Tg mice compared to WT mice.…”

“…In a model of angiotensin IIinduced hypertension, renal fibrosis develops through increased activity of CD73 and adenosine generation. The A 2B R is upregulated and downstream signalling markers such as hypoxia-inducible factor 1α (HIF-1α) and endothelin-1 (ET-1) promote fibrosis [12]. Together these data demonstrate the complex and inter-related roles of the purinergic and adenosinergic pathways in the UUO model.…”

Signaling pathways involving adenosine A2A and A2B receptors in wound healing and fibrosis

“…The A 2B receptor promotes renal fibrosis in the setting of hypoxia by induction of endothelin-1 expression [51]. Endothelin-1, in turn, promotes mesangial cell proliferation and collagen production in the kidney [52].…”

Dual A1/A2B Receptor Blockade Improves Cardiac and Renal Outcomes in a Rat Model of Heart Failure with Preserved Ejection Fraction

“…Therefore, blocking A 2B receptors should have little adverse effect on coronary flow, particularly in the presence of A 1 receptor antagonism. Also, although acute A 2B receptor stimulation inhibits growth of cardiac fibroblasts and vascular smooth muscle cells (Dubey et al, 1996(Dubey et al, , 1997(Dubey et al, , 1998a, longterm A 2B receptor stimulation promotes inflammation and fibrosis (Mustafa et al, 2007;Dai et al, 2011;Zhang et al, 2013). Thus, long-term antagonism of A 2B receptors could improve target organ histology.…”