β3 adrenergic receptor as potential therapeutic target in ADPKD

The β3-AR is a GPCR expressed in most segments of the murine nephron, where it modulates cAMP production. We investigate β3-AR potential as therapeutic target in ADPKD and show that targeted β3-AR blockade leads to a reduction in kidney/body weight through a decrease in total cAMP renal levels in a m ouse model of ADPKD. Furthermore we report evidence of β3-AR presence in biopsies from healthy and ADPKD patients. AbstractAutosomal dominant polycystic kidney disease (ADPKD) disrupts renal parenchyma through progressive expansion of fluid-filled cysts. The only approved pharmacotherapy for ADKPD involves the blockade of the vasopressin type 2 receptor (V2R). V2R is a GPCR expressed by a subset of renal tubular cells and whose activation stimulates cyclic AMP (cAMP) accumulation, which is a major driver of cyst growth. The β3-adrenergic receptor (β3-AR) is a GPCR expressed in most segments of the murine nephron, where it modulates cAMP production. Since sympathetic nerve activity, which leads to activation of the β3-AR, is elevated in patients affected by ADPKD, we hypothesize that β3-AR might constitute a novel t herapeutic target. We find that administration of the selective β3-AR antagonist SR59230A to an ADPKD mouse model (Pkd1fl/fl;Pax8rtTA;TetO-Cre) decreases cAMP levels, producing a significant reduction in kidney/body weight ratio and a partial improvement in kidney function. Furthermore, cystic mice show significantly higher β3-AR levels than healthy controls,...
Source: Physiological Reports - Category: Physiology Authors: Tags: ORIGINAL ARTICLE Source Type: research