Deiodinase-3 is a thyrostat to regulate podocyte homeostasis.
Animals
Cells, Cultured
Homeostasis
/ physiology
Humans
Integrin alphaVbeta3
/ metabolism
Iodide Peroxidase
/ metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Podocytes
/ metabolism
Proteinuria
/ metabolism
Puromycin Aminonucleoside
/ metabolism
Receptors, Thyrotropin
/ metabolism
Signal Transduction
/ physiology
Thyroid Hormones
/ metabolism
Triiodothyronine
/ metabolism
D3
Graves’ disease
deiodinases
integrin
kidney
podocytes
thyroid
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Oct 2021
Oct 2021
Historique:
received:
17
06
2021
revised:
22
09
2021
accepted:
22
09
2021
pubmed:
15
10
2021
medline:
8
2
2022
entrez:
14
10
2021
Statut:
ppublish
Résumé
Nephrotic syndrome (NS) is associated with kidney podocyte injury and may occur as part of thyroid autoimmunity such as Graves' disease. Therefore, the present study was designed to ascertain if and how podocytes respond to and regulate the input of biologically active thyroid hormone (TH), 3,5,3'-triiodothyronine (T3); and also to decipher the pathophysiological role of type 3 deiodinase (D3), a membrane-bound selenoenzyme that inactivates TH, in kidney disease. To study D3 function in healthy and injured (PAN, puromycin aminonucleoside and LPS, Lipopolysaccharide-mediated) podocytes, immunofluorescence, qPCR and podocyte-specific D3 knockout mouse were used. Surface plasmon resonance (SPR), co-immunoprecipitation and Proximity Ligation Assay (PLA) were used for the interaction studies. Healthy podocytes expressed D3 as the predominant deiodinase isoform. Upon podocyte injury, levels of Dio3 transcript and D3 protein were dramatically reduced both in vitro and in the LPS mouse model of podocyte damage. D3 was no longer directed to the cell membrane, it accumulated in the Golgi and nucleus instead. Further, depleting D3 from the mouse podocytes resulted in foot process effacement and proteinuria. Treatment of mouse podocytes with T3 phenocopied the absence of D3 and elicited activation of αvβ3 integrin signaling, which led to podocyte injury. We also confirmed presence of an active thyroid stimulating hormone receptor (TSH-R) on mouse podocytes, engagement and activation of which resulted in podocyte injury. The study provided a mechanistic insight into how D3-αvβ3 integrin interaction can minimize T3-dependent integrin activation, illustrating how D3 could act as a renoprotective thyrostat in podocytes. Further, injury caused by binding of TSH-R with TSH-R antibody, as found in patients with Graves' disease, explained a plausible link between thyroid disorder and NS. This work was supported by American Thyroid Association (ATA-2018-050.R1).
Sections du résumé
BACKGROUND
BACKGROUND
Nephrotic syndrome (NS) is associated with kidney podocyte injury and may occur as part of thyroid autoimmunity such as Graves' disease. Therefore, the present study was designed to ascertain if and how podocytes respond to and regulate the input of biologically active thyroid hormone (TH), 3,5,3'-triiodothyronine (T3); and also to decipher the pathophysiological role of type 3 deiodinase (D3), a membrane-bound selenoenzyme that inactivates TH, in kidney disease.
METHODS
METHODS
To study D3 function in healthy and injured (PAN, puromycin aminonucleoside and LPS, Lipopolysaccharide-mediated) podocytes, immunofluorescence, qPCR and podocyte-specific D3 knockout mouse were used. Surface plasmon resonance (SPR), co-immunoprecipitation and Proximity Ligation Assay (PLA) were used for the interaction studies.
FINDINGS
RESULTS
Healthy podocytes expressed D3 as the predominant deiodinase isoform. Upon podocyte injury, levels of Dio3 transcript and D3 protein were dramatically reduced both in vitro and in the LPS mouse model of podocyte damage. D3 was no longer directed to the cell membrane, it accumulated in the Golgi and nucleus instead. Further, depleting D3 from the mouse podocytes resulted in foot process effacement and proteinuria. Treatment of mouse podocytes with T3 phenocopied the absence of D3 and elicited activation of αvβ3 integrin signaling, which led to podocyte injury. We also confirmed presence of an active thyroid stimulating hormone receptor (TSH-R) on mouse podocytes, engagement and activation of which resulted in podocyte injury.
INTERPRETATION
CONCLUSIONS
The study provided a mechanistic insight into how D3-αvβ3 integrin interaction can minimize T3-dependent integrin activation, illustrating how D3 could act as a renoprotective thyrostat in podocytes. Further, injury caused by binding of TSH-R with TSH-R antibody, as found in patients with Graves' disease, explained a plausible link between thyroid disorder and NS.
FUNDING
BACKGROUND
This work was supported by American Thyroid Association (ATA-2018-050.R1).
Identifiants
pubmed: 34649077
pii: S2352-3964(21)00410-2
doi: 10.1016/j.ebiom.2021.103617
pmc: PMC8517284
pii:
doi:
Substances chimiques
Integrin alphaVbeta3
0
Receptors, Thyrotropin
0
Thyroid Hormones
0
Triiodothyronine
06LU7C9H1V
Puromycin Aminonucleoside
58-60-6
iodothyronine deiodinase type III
EC 1.11.1.-
Iodide Peroxidase
EC 1.11.1.8
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
103617Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK077148
Pays : United States
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest Jochen Reiser has patents on novel strategies for kidney therapeutics and stands to gain royalties from their commercialization. He is the co-founder of Walden Biosciences (Cambridge, MA, USA), a biotechnology company in which he has financial interest, including stock. Antonio Bianco is a consultant for Synthonics, Allergan, Abbvie, and BLA Technology. Other authors have nothing to disclose and there are no competing or conflicting interests.