Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

A Mutation in γ-Adducin Impairs Autoregulation of Renal Blood Flow and Promotes the Development of Kidney Disease. J Am Soc Nephrol 2020 04;31(4):687-700

Date

02/08/2020

Pubmed ID

32029431

Pubmed Central ID

PMC7191921

DOI

10.1681/ASN.2019080784

Scopus ID

2-s2.0-85082881644   8 Citations

Abstract

BACKGROUND: The genes and mechanisms involved in the association between diabetes or hypertension and CKD risk are unclear. Previous studies have implicated a role for γ-adducin (ADD3), a cytoskeletal protein encoded by Add3.

METHODS: We investigated renal vascular function in vitro and in vivo and the susceptibility to CKD in rats with wild-type or mutated Add3 and in genetically modified rats with overexpression or knockout of ADD3. We also studied glomeruli and primary renal vascular smooth muscle cells isolated from these rats.

RESULTS: This study identified a K572Q mutation in ADD3 in fawn-hooded hypertensive (FHH) rats-a mutation previously reported in Milan normotensive (MNS) rats that also develop kidney disease. Using molecular dynamic simulations, we found that this mutation destabilizes a critical ADD3-ACTIN binding site. A reduction of ADD3 expression in membrane fractions prepared from the kidney and renal vascular smooth muscle cells of FHH rats was associated with the disruption of the F-actin cytoskeleton. Compared with renal vascular smooth muscle cells from Add3 transgenic rats, those from FHH rats had elevated membrane expression of BKα and BK channel current. FHH and Add3 knockout rats exhibited impairments in the myogenic response of afferent arterioles and in renal blood flow autoregulation, which were rescued in Add3 transgenic rats. We confirmed these findings in a genetic complementation study that involved crossing FHH and MNS rats that share the ADD3 mutation. Add3 transgenic rats showed attenuation of proteinuria, glomerular injury, and kidney fibrosis with aging and mineralocorticoid-induced hypertension.

CONCLUSIONS: This is the first report that a mutation in ADD3 that alters ACTIN binding causes renal vascular dysfunction and promotes the susceptibility to kidney disease.

Author List

Fan F, Geurts AM, Pabbidi MR, Ge Y, Zhang C, Wang S, Liu Y, Gao W, Guo Y, Li L, He X, Lv W, Muroya Y, Hirata T, Prokop J, Booz GW, Jacob HJ, Roman RJ

Author

Aron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Calmodulin-Binding Proteins
Disease Models, Animal
Homeostasis
Hypertension
Kidney Diseases
Kidney Glomerulus
Male
Muscle, Smooth, Vascular
Mutation
Myocytes, Smooth Muscle
Rats
Rats, Sprague-Dawley
Rats, Transgenic
Renal Circulation