Reduced 11β-Hydroxysteroid Dehydrogenase Activity in the Remaining Kidney Following Nephrectomy*

Abstract

Abstract Intracellular access of steroids to gluco- and mineralocorticoid receptors is regulated by reduced 11β-hydroxysteroid dehydrogenase (OHSD) 1 and 2. These enzymes convert active 11β-OH-steroids into inactive 11-keto-steroids. The purpose of the present study was to establish whether the 11β-OHSD1 and 11β-OHSD2 are modulated in the remnant kidney 24 h or 14 days after uninephrectomy (UNX) in rats. Overall, 11β-OHSD activity was analyzed by measuring the ratio of the exogenous 11β-OH-steroid prednisolone to its 11-keto metabolite prednisone in vivo in kidney tissue using high performance liquid chromatography. To determine which isoenzyme accounts for the changed activity 24 h after UNX, the oxidation and reduction attributable to 11β-OHSD1 and oxidation to 11β-OHSD2 were analyzed in total renal extracts and in isolated glomeruli, proximal convoluted tubules (PCT), cortical ascending limbs, and cortical convoluted tubules (CCT). The messenger RNA content of 11β-OHSD1 and 11β-OHSD2 was measured by RT-PCR in renal tissues and single segments, using glyceraldehyde-3-phosphate-dehydrogenase as an internal standard. Protein amounts of 11β-OHSD1 and 11β-OHSD2 were assessed by Western blot. The prednisolone/prednisone ratio increased 24 h after UNX in 9 out of 10 animals (P ≤ 0.0011), and was unchanged 14 days after UNX. 11β-OHSD1 oxidation (P ≤ 0.032) and reduction activity (P ≤ 0.002) declined 24 h after UNX in total extracts. 11β-OHSD1 oxidase activity was more than 3 times higher in PCT than in glomeruli, cortical ascending limbs, and CCT, and declined by 50% after UNX (P ≤ 0.001). The reductase activity did not change following UNX in PCT. 11β-OHSD2 activity was 5–15 times higher in CCT than in the other segments, and decreased significantly after UNX (P ≤ 0.008). UNX did not affect messenger RNA and protein levels of both enzymes in total renal extracts. In conclusion, 11β-OHSD1 and 11β-OHSD2 are predominantly expressed in PCT and CCT, respectively, and their corresponding oxidative activities decline after UNX. Thus, the access of 11β-glucocorticosteroids to gluco- and mineralocorticoid receptors in the remaining kidney is facilitated after UNX.