β3 adrenergic receptor as potential therapeutic target in ADPKD.

Abstract

Autosomal 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 therapeutic 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, suggesting a correlation between receptor expression and disease development. Finally, β3-AR is expressed in human renal tissue and localizes to cyst-lining epithelial cells in patients. Thus, β3-AR is a potentially interesting target for the development of new treatments for ADPKD.

• Authors: Giorgia Schena, Monica Carmosino, Samantha Chiurlia, Laura Onuchic, Mauro Mastropasqua, Eugenio Maiorano, Francesco P Schena, Michael J Caplan
• Journal: Physiological reports (Physiol Rep) Vol. 9 Issue 20 Pg. e15058 (10 2021) ISSN: 2051-817X [Electronic] United States
• PMID: 34676684 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.

Chemical References

• 3-(2-ethylphenoxy)-1-(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanol oxalate
• Adrenergic beta-3 Receptor Antagonists
• Propanolamines
• Receptors, Adrenergic, beta-3
• Cyclic AMP

Topics

• Adrenergic beta-3 Receptor Antagonists (pharmacology)
• Animals
• Case-Control Studies
• Cell Proliferation
• Cells, Cultured
• Cyclic AMP (metabolism)
• Epithelial Cells (drug effects, metabolism, pathology)
• Humans
• Kidney (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Knockout
• Polycystic Kidney, Autosomal Dominant (drug therapy, etiology, metabolism, pathology)
• Propanolamines (pharmacology)
• Receptors, Adrenergic, beta-3 (chemistry)