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Cullin-3 regulates the renal baroreceptor machinery that controls renin gene expression. JCI Insight 2025 Aug 08;10(15)

Date

07/08/2025

Pubmed ID

40627460

Pubmed Central ID

PMC12333948

DOI

10.1172/jci.insight.194075

Scopus ID

2-s2.0-105013217775 (requires institutional sign-in at Scopus site)

Abstract

Mutations in Cullin-3 (CUL3) cause hypertension (HTN). We examined the role of smooth muscle cell (SMC) CUL3 in the regulation of renin gene expression. Mice with SMC-specific CUL3 deletion (S-CUL3-KO) developed severe HTN with paradoxically preserved levels of plasma angiotensin peptides and renal renin expression. Cre-recombinase was active in juxtaglomerular (JG) cells, resulting in decreased CUL3 expression. We evaluated components of the renin cell baroreceptor and revealed preserved Lamin A/C but decreased integrin β1 expression in S-CUL3-KO. We hypothesized that Rab proteins are involved in integrin β1 downregulation. Silencing either Rab21 or Rab5 in CUL3-deficient HEK293 cells increased integrin β1 protein. Coimmunoprecipitation revealed a direct interaction between Rab5 and CUL3. CUL3 deficiency increased Rab5, suggesting it is regulated by a CUL3-mediated mechanism and that CUL3 deficiency results in loss of Rab protein turnover, leading to enhanced integrin β1 internalization. We conclude that the loss of integrin β1 from JG cells impairs the mechanosensory function of the renin cell baroreceptor, which underlies the persistent renin expression observed in hypertensive S-CUL3-KO mice. These findings provide insights into the molecular mechanisms of HTN, revealing that dysregulation of Rab proteins and integrin β1 in the kidney due to CUL3 deficiency contributes to the development of HTN.

Author List

Golosova D, Kumar G, Lu KT, Muskus Veitia PC, Hantke Guixa A, Wackman KK, Fekete EM, Brozoski DT, Grobe JL, Sequeira-Lopez MLS, Gomez RA, Nakagawa P, Sigmund CD

Authors

Justin L. Grobe PhD Professor in the Physiology department at Medical College of Wisconsin
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin




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

Animals
Cullin Proteins
Gene Expression Regulation
HEK293 Cells
Humans
Hypertension
Integrin beta1
Juxtaglomerular Apparatus
Kidney
Male
Mice
Mice, Knockout
Myocytes, Smooth Muscle
Pressoreceptors
Renin
rab5 GTP-Binding Proteins