Salt loading decreases urinary excretion and increases intracellular accumulation of uromodulin in stroke-prone spontaneously hypertensive rats

Mary, S. , Boder, P., Rossitto, G., Graham, L., Scott, K., Flynn, A., Kipgen, D., Graham, D. and Delles, C. (2021) Salt loading decreases urinary excretion and increases intracellular accumulation of uromodulin in stroke-prone spontaneously hypertensive rats. Clinical Science, 125(24), pp. 2749-2761. (doi: 10.1042/CS20211017) (PMID:34870708)

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Abstract

Uromodulin (UMOD) is the most abundant renal protein secreted into urine by the thick ascending limb (TAL) epithelial cells of the loop of Henle. Genetic studies have demonstrated an association between UMOD risk variants and hypertension. We aimed to dissect the role of dietary salt in renal UMOD excretion in normotension and chronic hypertension. Normotensive Wistar–Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) (n=8/sex/strain) were maintained on 1% NaCl for 3 weeks. A subset of salt-loaded SHRSP was treated with nifedipine. Salt-loading in SHRSP increased blood pressure (ΔSBP 35 ± 5 mmHg, P<0.0001) and kidney injury markers such as kidney injury marker-1 (KIM-1; fold change, FC 3.4; P=0.003), neutrophil gelatinase-associated lipocalin (NGAL; FC, 2.0; P=0.012) and proteinuria. After salt-loading there was a reduction in urinary UMOD excretion in WKY and SHRSP by 26 and 55% respectively, compared with baseline. Nifedipine treatment reduced blood pressure (BP) in SHRSP, however, did not prevent salt-induced reduction in urinary UMOD excretion. In all experiments, changes in urinary UMOD excretion were dissociated from kidney UMOD protein and mRNA levels. Colocalization and ex-vivo studies showed that salt-loading increased intracellular UMOD retention in both WKY and SHRSP. Our study provides novel insights into the interplay among salt, UMOD, and BP. The role of UMOD as a cardiovascular risk marker deserves mechanistic reappraisal and further investigations based on our findings.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Graham, Dr Delyth and Boder, Philipp and Samji, Dr Sheon and Rossitto, Dr Giacomo and Scott, Kayley and Graham, Dr Lesley and Delles, Professor Christian and Flynn, Mr Arun
Creator Roles:
Mary, S.Conceptualization, Resources, Data curation, Software, Formal analysis, Funding acquisition, Validation, Investigation, Visualization, Writing – original draft, Project administration, Writing – review and editing
Boder, P.Software, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review and editing
Rossitto, G.Conceptualization, Data curation, Software, Formal analysis, Investigation, Writing – review and editing
Graham, L.Conceptualization, Writing – review and editing
Scott, K.Investigation, Methodology
Flynn, A.Visualization, Methodology
Graham, D.Supervision, Validation, Methodology, Writing – review and editing
Delles, C.Conceptualization, Resources, Data curation, Supervision, Funding acquisition, Writing – original draft, Project administration, Writing – review and editing
Authors: Mary, S., Boder, P., Rossitto, G., Graham, L., Scott, K., Flynn, A., Kipgen, D., Graham, D., and Delles, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Clinical Science
Publisher:Portland Press
ISSN:0143-5221
ISSN (Online):1470-8736
Published Online:06 December 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Clinical Science 125(24): 2749-2761
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190814BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177Institute of Cardiovascular & Medical Sciences
303944BHF Centre of ExcellenceRhian TouyzBritish Heart Foundation (BHF)RE/18/6/34217CAMS - Cardiovascular Science
305659BHF 4-Year PhD Studentship Award 2018Rhian TouyzBritish Heart Foundation (BHF)FS/18/58/34179CAMS - Cardiovascular Science
306830Defining the roles of dimethylarginine dimethylaminohydrolases (DDAH) in cerebrovascular regulationAlyson MillerBritish Heart Foundation (BHF)FS/19/40/34477CAMS - Cardiovascular Science
302108BHF 4-Year PhD Studentship Award 2017Rhian TouyzBritish Heart Foundation (BHF)FS/17/63/33485CAMS - Cardiovascular Science