Deiodinase-3 is a thyrostat to regulate podocyte homeostasis
| Autor: | Steve Mangos, Domenico Salvatore, Jochen Reiser, Ranadheer Reddy Dande, Kwi Hye Koh, Antonio C. Bianco, Chuang Chen, Joao Pedro WerneckdeCastro, Yashwanth Reddy Sudhini, Cristina Luongo, Nicholas J. Tardi, Beata Samelko, Shivangi Agarwal, Mehmet M. Altintas |
|---|---|
| Přispěvatelé: | Agarwal, S., Koh, K. H., Tardi, N. J., Chen, C., Dande, R. R., Werneckdecastro, J. P., Sudhini, Y. R., Luongo, C., Salvatore, D., Samelko, B., Altintas, M. M., Mangos, S., Bianco, A., Reiser, J. |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
deiodinase
Male Medicine (General) podocyte Research paper Graves' disease Puromycin Aminonucleoside Podocyte thyroid Mice IOP iopanoic acid Homeostasis Cells Cultured TH thyroid hormone or T3 Mice Knockout T4 Thyroxine Triiodothyronine biology Chemistry Podocytes Glomerular basement membrane Thyroid deiodinases Receptors Thyrotropin General Medicine Cell biology Proteinuria medicine.anatomical_structure Knockout mouse PM plasma membrane Medicine D3 GBM glomerular basement membrane Signal Transduction Cell signaling medicine.medical_specialty kidney Thyroid Hormones FP foot process integrin T2 3 3′-diiodothyronine MCD minimal change disease Deiodinase D3 Type 3 iodothyronine selenodeiodinase PAN puromycin aminonucleoside Iodide Peroxidase General Biochemistry Genetics and Molecular Biology DN diabetic nephropathy R5-920 Internal medicine medicine NS nephrotic syndrome TSH-R Thyroid stimulating hormone receptor Animals Humans rT3 reverse-3 3′ 5′-triiodothyronine business.industry FSGS focal segmental glomerulosclerosis CKD chronic kidney disease Institutional Animal Care and Use Committee medicine.disease Integrin alphaVbeta3 Thyroid disorder D1 Type 1 iodothyronine selenodeiodinase Mice Inbred C57BL Endocrinology T3 3 5 3′-triiodothyronine Sec selenocysteine biology.protein LPS lipopolysaccharides D2 Type 2 iodothyronine selenodeiodinase business Graves’ disease |
| Zdroj: | EBioMedicine EBioMedicine, Vol 72, Iss, Pp 103617-(2021) |
| ISSN: | 2352-3964 |
| Popis: | 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: 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: 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: 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: Funding support from American Thyroid Association (ATA) to NJT (ATA-2018-050.R1). Declaration of 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. Other authors have nothing to disclose and there are no competing or conflicting interests. Ethical Approval: All animal experiments were carried out according to the NIH’s Guide for the Care and Use of Experimental Animals (National Academies Press, 2011), and approved by the Institutional Animal Care and Use Committee (IACUC) at Rush University (Chicago, Illinois, USA). Human biopsy kidney sections from healthy donors and patients with FSGS, DN and MCD were procured in accordance with guidelines on human research and with approval of the Institutional Review Board of Rush University Medical Center (Chicago, Illinois, USA). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|