Abstract 125: Elevated Cd73-mediated Increased Renal Adenosine Signaling Contributes to Chronic Hypertensive Nephropathy via A2b Adenosine Receptor
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. Here we sought to identify specific factors and signaling pathways that contribute to hypertensive CKD and thereby exacerbate disease progression. Using non-biased high throughput quantitative RT-PCR 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 (Ang II)-infused mice, a well-accepted animal model of hypertensive nephropathy. Similarly, in human, we found that CD73 levels were significantly elevated in the kidneys of CKD patients compared to normal individuals and further elevated in hypertensive CKD patients. Next, we provide both genetic and pharmacological evidence that elevated CD73 contributes to Ang II-induced hypertension, kidney injury and progression to renal fibrosis by chronic elevation of adenosine locally in the kidney (from 1.275±0.44 to 4.278±0.84 nmole/mg protein), but not systemically in the circulation. Mechanistically, we showed that excess renal adenosine preferentially activated the A2B adenosine receptor (ADORA2B) and that selective inhibition of the ADORA2B or genetic deficiency of the ADORA2B significantly reduces hypertension (168±12 to 120±15 mmHg) and proteinuria (75±14 to 25±5 μg albumin/mg creatinine), while increasing urinary osmolarity (780±105 to 2145±156, all P<0.05) and halts progression to renal fibrosis in Ang II-infused mice. These findings led us to further discover that adenosine signaling via ADORA2B activation stimulates kidney production of endothelin-1, a potent vasoconstrictor, in a HIF-1α-dependent manner and underlies the pathogenesis of the disease. Overall, our studies reveal that CD73-mediated chronic elevation of renal adenosine is a prominent driver of hypertensive CKD and inhibition of excess adenosine-mediated ADORA2B signaling is a novel therapeutic target for the disease.
- © 2012 by American Heart Association, Inc.