LOCALIZATION OF RENAL 11-BETA-DEHYDROGENASE BY INSITU HYBRIDIZATION - AUTOCRINE NOT PARACRINE PROTECTOR OF THE MINERALOCORTICOID RECEPTOR

In the kidney, 11-beta-dehydrogenase (11-beta-DH) converts the active steroid cortisol to inactive cortisone (corticosterone to 11-dehydrocorticosterone in the rat). In man, congenital and acquired deficiency of 11-beta-dehydrogenase are rare causes of hypertension in which cortisol acts as a potent mineralocorticoid. Observations from these clinical studies indicate that 11-beta-DH conveys specificity for the mineralocorticoid receptor in distal tubules and collecting ducts. However, while some studies do indicate 11-beta-DH activity in rat distal tubules and collecting ducts, immunohistochemical studies localize 11-beta-DH only to proximal tubules. To resolve this dilemma, we have performed in situ hybridization localization of 11-beta-DH mRNA in rat kidney tissue using S-35-labeled sense and antisense cRNA probes to rat 11-beta-DH. In contrast to our immunohistochemical studies in which 11-beta-DH protein was localized predominantly to proximal tubules in the inner cortex, 11-beta-DH mRNA was expressed in tubules in both the inner and outer cortex, most probably proximal and distal tubules, and in collecting ducts extending across the corticomedullary junction to the papillary tip. Weak hybridization was also seen in glomeruli, but no hybridization to the sense 11-beta-DH cRNA or to sections pretreated with RNAase-A was observed. We conclude that renal 11-beta-DH is suitably located to prevent access of glucocorticoid to the MR in an autocrine and not a paracrine fashion. 11-beta-DH in proximal tubules may protect the glucocorticoid receptor.