Modulation of 11 -hydroxysteroid dehydrogenase 1 by 2-adrenoceptor in the ischaemia-reperfused rat kidney

Abstract

11β-Hydroxysteroid dehydrogenase Type 1 (11βHSD-1) amplifies intracellular levels of active glucocorticoids which possess protective effects against organ ischaemia and reperfusion (I/R). However, the mechanisms by which 11βHSD-1 is modified after a renal I/R challenge remain unclear. This study investigated the effect of β(2)-adrenoceptor (β(2)-AR) activation and the subsequent signalling pathways on renal 11βHSD-1 gene expression following renal I/R. Renal I/R was induced using 25 min of bilateral renal artery occlusion in 4-week-old Wistar rats followed by an intraperitoneal injection of various doses of adeno-β(2)-AR gene. Following renal I/R, kidneys, plasma and urine were collected to assay 11βHSD messenger RNA (mRNA) levels, β(2)-AR signalling cascades and renal function. On the second day after the renal I/R challenge, there was a reduction in renal 11βHSD-1 mRNA levels associated with a decrease in stimulatory G protein α (Gsα) and adenylate cyclase-1 (ACY-1) in the kidney. The addition of the adeno-β(2)-AR gene resulted in greater increases in 11βHSD-1 mRNA and β(2)-AR-Gsα-ACY-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) activity in the kidney but had no effect on 11βHSD-2 mRNA or protein kinase C levels in the kidney. Over-expression of β(2)-AR resulting from the gene delivery improved renal function and 11βHSD-1 production following renal I/R, which were actions exerted through the cAMP-PKA pathway. The stimulatory effect of functional β(2)-AR activation on renal 11βHSD-1 expression may offer a means of protection from renal I/R injury.