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A profile of multiple circulating tumor necrosis factor receptors associated with early progressive kidney decline in Type 1 Diabetes is similar to profiles in autoimmune disorders.

ABSTRACT: This study comprehensively evaluated the association between known circulating tumor necrosis factor (TNF) superfamily ligands and receptors and the development of early progressive kidney decline (PKD) leading to end-stage kidney disease (ESKD) in Type 1 diabetes. Participants for the study were from the Macro-Albuminuria Study (198 individuals), and the Micro-Albuminuria Study (148 individuals) of the Joslin Kidney Study. All individuals initially had normal kidney function and were followed for seven-fifteen years to determine the slope of the estimate glomerular filtration rate and to ascertain onset of ESKD. Plasma concentrations of 25 TNF superfamily proteins were measured using proximity extension assay applied in the OLINK proteomics platform. In the both studies risk of early PKD, determined as estimated glomerular filtration rate loss greater than or equal to three ml/min/1.73m²/year, was associated with elevated circulating levels of 13 of 19 TNF receptors examined. In the Macro-Albuminuria Study, we obtained similar findings for risk of progression to ESKD. These receptors comprised: TNF-R1A, -R1B, -R3, -R4, -R6, -R6B, -R7, -R10A, -R10B, -R11A, -R14, -R21, and -R27. Serial measurements showed that circulating levels of these TNF receptors had increased before the onset of PKD. In contrast, none of the six measured TNF ligands showed association with risk of early PKD. Of significance, the disease process that underlies PKD leading to ESKD in Type 1 diabetes has a profile also seen in autoimmune disorders. The mechanisms of this enrichment may be causally related to the development of PKD in Type 1 diabetes and must be investigated further. Thus, some of these receptors may be used as new risk predictors of ESKD.

SUBMITTER: Ihara K

PROVIDER: S-EPMC7891866 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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A profile of multiple circulating tumor necrosis factor receptors associated with early progressive kidney decline in Type 1 Diabetes is similar to profiles in autoimmune disorders.

Ihara Katsuhito K Skupien Jan J Krolewski Bozena B Md Dom Zaipul I ZI O'Neil Kristina K Satake Eiichiro E Kobayashi Hiroki H Rashidi Narges M NM Niewczas Monika A MA Krolewski Andrzej S AS

Kidney international 20200725 3

This study comprehensively evaluated the association between known circulating tumor necrosis factor (TNF) superfamily ligands and receptors and the development of early progressive kidney decline (PKD) leading to end-stage kidney disease (ESKD) in Type 1 diabetes. Participants for the study were from the Macro-Albuminuria Study (198 individuals), and the Micro-Albuminuria Study (148 individuals) of the Joslin Kidney Study. All individuals initially had normal kidney function and were followed f ...[more]

PMID: 32717193

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Project description:Tumor necrosis factor (TNF) is associated with several neurodegenerative disorders including multiple sclerosis (MS). Although TNF-targeted therapies have been largely unsuccessful in MS, recent preclinical data suggests selective soluble TNF inhibition can promote remyelination. This has renewed interest in regulation of TNF signaling in demyelinating disease, especially given the limited treatment options for progressive MS. Using a mouse model of progressive MS, this study evaluates the effects of sustained TNF on oligodendrocyte (OLG) apoptosis and OLG precursor cell (OPC) differentiation.Induction of experimental autoimmune encephalomyelitis (EAE) in transgenic mice expressing a dominant-negative interferon-? receptor under the human glial fibrillary acidic protein promoter (GFAP?R1?) causes severe non-remitting disease associated with sustained TNF. Therapeutic effects in GFAP?R1? mice treated with anti-TNF compared to control antibody during acute EAE were evaluated by assessing demyelinating lesion size, remyelination, OLG apoptosis, and OPC differentiation.More severe and enlarged demyelinating lesions in GFAP?R1? compared to wild-type (WT) mice were associated with increased OLG apoptosis and reduced differentiated CC1+Olig2+ OLG within lesions, as well as impaired upregulation of TNF receptor-2, suggesting impaired OPC differentiation. TNF blockade during acute EAE in GFAP?R1? both limited OLG apoptosis and enhanced OPC differentiation consistent with reduced lesion size and clinical recovery. TNF neutralization further limited increasing endothelin-1 (ET-1) expression in astrocytes and myeloid cells noted in lesions during disease progression in GFAP?R1? mice, supporting inhibitory effects of ET-1 on OPC maturation.Our data implicate that IFN? signaling to astrocytes is essential to limit a detrimental positive feedback loop of TNF and ET-1 production, which increases OLG apoptosis and impairs OPC differentiation. Interference of this cycle by TNF blockade promotes repair independent of TNFR2 and supports selective TNF targeting to mitigate progressive forms of MS.

Dataset Information

A profile of multiple circulating tumor necrosis factor receptors associated with early progressive kidney decline in Type 1 Diabetes is similar to profiles in autoimmune disorders.

Publications

A profile of multiple circulating tumor necrosis factor receptors associated with early progressive kidney decline in Type 1 Diabetes is similar to profiles in autoimmune disorders.

Similar Datasets

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