Regulation of renal organic anion transporter expression and function in ACTH‐treated mice

Abstract

Our previous renal microarray studies indicated differential expression of genes encoding organic anion transporters in a mouse model of ACTH‐dependent Cushing syndrome (Physiological Genomics 40: 158, 2010). In the current study, we used quantitative PCR to show significantly (P<0.01) reduced expression of genes encoding OATP‐1 (slco1a1), OAT2 (slc22a7) and OAT3 (slc22a8) in the kidneys of ACTH‐treated mice (n=6/6). In separate groups of mice, a 14‐day treatment with ACTH (n=5) caused hypertension, polyuria and a four‐fold increase in uric acid excretion, compared to controls (n=6). This is consistent with down‐regulation of OAT3, which contributes to the reabsorption of uric acid. ACTH‐treated mice also had a significantly reduced renal clearance of p‐aminohippurate (cPAH), a prototypical substrate of the OAT system. Since cPAH was not affected by co‐administration of probenecid, it is likely that organic anions normally secreted via this pathway are largely excreted by filtration during chronic glucocorticoid excess. These data indicate that organic anion transport in the kidney is physiologically regulated by corticosteroids. Since several classes of drugs are excreted via this pathway, our data have therapeutic implications in conditions of steroid excess.