Background: Hyperuricemia is often associated with chronic kidney diseases (CKD) and is considered as an independent risk factor of cardiovascular and renal diseases. Urate transporter 1 (URAT1), organic anion transporter 1 (OAT1) and OAT3 are believed to play pivotal roles on urate excretion in kidneys. Activation of RAAS in the kidney plays a key role in the pathophysiology of CKD. Thus, we hypothesized that RAAS may be involved in hyperuricemia in patients with CKD by effecting the three transporters on their expression.
Objective: To explore whether angiotensin II or aldosterone have an effect on expression of the three transporters in human proximal tubular (HKC) cells.
Methods: HKC cells were stimulated by angiotensin II or aldosterone with different concentration and time, and expression of the three transporters and the three subfamilies of MAP kinases (ERK, p38 and JNK) were detected by Western blot analysis. ERK kinase inhibitor U0126 and mineralocorticoid receptor (MR) antagonist spironolactone were also used to clarify whether ERK1/2 and MR were involved in this process.
Results: Aldosterone, but not angiotensin II, significantly increased URAT1 expression in a time-and dose-dependent manner. Treatment with aldosterone also led to potent activation of ERK1/2, but not JNK or p38. These effects could be prevented by pretreatment with U0126, while could not be prevented by spironolactone. We also found that MR could not be detected in HKC cells, but it was readily detected in collecting duct cells by RT-PCR and Western blot analysis.
Conclusions: Upregulation of URAT1 may be responsible for hyperuricemia in patients with CKD. Aldosterone plays a pivotal role in the upregulation of URAT1 in HKC cells via activation of ERK1/2 MAP kinase and mediated by a nongenomic signaling pathway of aldosterone, i.e. independent of MR. These results suggest that ERK1/2 may be a molecular target for drug development to treat patients with hyperuricemia.