Human renal 11β-hydroxysteroid dehydrogenase 1 functions and co-localizes with COX-2

Abstract

The local renal metabolism of glucocorticoids (GCs) by isoforms of 11β-hydroxysteroid dehydrogenase (11β-HSD1 and 11β-HSD2) determines their biological effects. 11β-HSD2, located in collecting duct epithelial cells of the mammalian and human kidney, serves as a putative “guardian” preventing GCs from binding to mineralocorticoid receptors. Various investigators have shown that both isoforms are present in kidney tissue from the rat, dog and other mammals. There is controversy as to whether 11β-HSD1 exists and functions in human kidney. The current studies examine the locale and function of both isoforms in human kidney. The expression of 11β-HSD1 was similar to that of 11β-HSD2 by Western blot. Two distinct Lineweaver Burke plots could be drawn providing enzyme kinetics for both isoforms. The apparent Km for the NADP dependent 11β-HSD1 enzyme was 0.42 μM while the apparent Km for the NAD dependent 11β-HSD2 enzyme was 10.2 nM. Human renal 11β-HSD1 appears to function as a dehydrogenase with no significant “reverse” reductase activity. Using immuno-histochemistry and Western blot analysis, 11β-HSD1 was found to co-localize with COX-2 in proximal tubule cells; COX-2 was not seen with 11β-HSD2 in cortical collecting duct. Thus, normal human kidney contains active 11β-HSD1 and 11β-HSD2. 11β-HSD1 co-localizes with COX-2 in proximal tubule cells.