Dopamine D2 receptor decreases the toxic effects of aristolochic acid in human renal proximal tubule cells.

Abstract

Previous work from our laboratory indicates that the renal dopamine D2 receptor (D2R) has a direct role in regulating renal inflammation and injury and blood pressure. In mice, renal‐selective D2R silencing increased the expression of pro‐inflammatory and pro‐fibrotic factors including TNFα, chemokine CCL‐2, TGFβ, fibronectin 1 (Fn1), and collagen 1α1 (Col1α1). Moreover, the damaging effects of 45‐minute bilateral ischemia/reperfusion on renal expression of profibrotic factors, renal function, and blood pressure in mice were ameliorated by a renal‐selective increase in D2R expression by the retrograde ureteral infusion of a viral vector carrying DRD2. In human renal proximal tubule cells (hRPTCs), D2R silencing increased the expression of TGFβ, Fn1 and Col1α1. We tested the hypothesis that in hRPTCs, D2R agonism decreases the deleterious effects of aristolochic acid, a potent nephrotoxic. hRPTCs were treated with aristolochic acid (5μg/ml, 24 hrs) in the presence or absence of the D2R agonist quinpirole (0.5 μM). Treatment with aristolochic acid increased the mRNA expression of TGFβ (1.3 ± 0.02; n=3; P<0.05), Fn1 (2.6 ±0.4‐fold, n=3, P<0.05), Col1α1 (1.9±0.2‐fold; n=3; P<0.05), and connective tissue growth factor (CTGF, 7.6 ± 0.3‐fold, n=3, P<0.05). Treatment with quinpirole, alone, decreased significantly the mRNA expression of TGFβ (0.7±0.05‐fold, n=3, P<0.05) and Fn1 (0.8±0.01‐fold, n=3, P<0.05) but did not change the expression of Col1α1, or CTCG. However, quinpirole reduced significantly the aristolochic‐mediated increase in the expression of Fn1 by 43% and Col1α1 by 35% but had no significant effect on that of TGFβ or CTGF. Our results indicate that several pathways are involved in the nephrotoxic effects of aristolochic acid and that D2R agonism is able to negatively regulate some but not all of those pathways.Support or Funding InformationThis work was funded by grants from the NIH: R01DK090918, P01HL074940, P01HL068686, R01HL092196, R37HL023081, and R01DK039308.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.