Cargando…
Serum α-KL, a potential early marker of diabetes complications in youth with T1D, is regulated by miRNA 192
Despite the wealth of information on biomarkers of diabetes complications in adults with type 1 diabetes, data in the pediatric population is limited. Diabetic nephropathy (DN), the leading cause of mortality in type 1 diabetes T1D), could be potentially missed in youth, as albuminuria, the current...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9388782/ https://www.ncbi.nlm.nih.gov/pubmed/35992154 http://dx.doi.org/10.3389/fendo.2022.937093 |
_version_ | 1784770288022454272 |
---|---|
author | Gong, Zhenwei Banchs, Pedro A. Pagán Liu, Ye Fu, Haoyi Arena, Vincent C. Forno, Erick Libman, Ingrid Ho, Jacqueline Muzumdar, Radhika |
author_facet | Gong, Zhenwei Banchs, Pedro A. Pagán Liu, Ye Fu, Haoyi Arena, Vincent C. Forno, Erick Libman, Ingrid Ho, Jacqueline Muzumdar, Radhika |
author_sort | Gong, Zhenwei |
collection | PubMed |
description | Despite the wealth of information on biomarkers of diabetes complications in adults with type 1 diabetes, data in the pediatric population is limited. Diabetic nephropathy (DN), the leading cause of mortality in type 1 diabetes T1D), could be potentially missed in youth, as albuminuria, the current “gold” standard, may be transient and may not reflect permanent renal impairment. Soluble alpha KL has emerged as a potential marker of early diabetic nephropathy. Seventy-nine pediatric patients with type 1 diabetes meeting ISPAD criteria for nephropathy screening were consecutively recruited (90% Caucasian, 51% male, mean age 16.1 ± 3.1 years, duration of T1D 7.2 ± 3.9 years, 2-year average HbA1c 8.0 ± 1.3%, and serum and urine samples were collected for analysis. Serum Klotho (KL) and circulating miRNA levels of select miRNA involved in the pathogenesis of DN were estimated. KL had a strong inverse correlation with diabetes duration and HbA1c, two important risk factors in the development of diabetes complications. Serum miR-192 were negatively associated with KL among children with prolonged duration of diabetes (≥12 years) after adjustment for age and sex. In cell culture, overexpression of miR-192 significantly downregulated KL mRNA and protein levels, and reduced KL levels in the media. miR-192 mimic reduced luciferase activity in a reporter containing the KL 3’ UTR (60% compared to controls, p<0.01), and the inhibitor rescued it. Deletion of a potential binding site for miR-192 in the KL 3’UTR completely abolished the effect of miR-192 in the reporter assay, suggesting that KL is a direct target gene of miR-192. Overexpression of miR-192 significantly increased oxidative stress (MDA) and expression of inflammatory and senescence markers IL-6 and p16. Inhibition of miR-192 significantly reduced levels of MDA, IL-6 and p16. In summary, we demonstrate an increase in miR-192 and a decrease in KL levels in children with prolonged duration of T1D. We demonstrate a novel role for miR-192 in directly regulating KL levels, and through that, senescence and oxidative stress, key pathological processes in the development of DN. miR-192 and/or KL levels are altered with severity and duration of diabetes and could serve as early biomarkers for DN. |
format | Online Article Text |
id | pubmed-9388782 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93887822022-08-20 Serum α-KL, a potential early marker of diabetes complications in youth with T1D, is regulated by miRNA 192 Gong, Zhenwei Banchs, Pedro A. Pagán Liu, Ye Fu, Haoyi Arena, Vincent C. Forno, Erick Libman, Ingrid Ho, Jacqueline Muzumdar, Radhika Front Endocrinol (Lausanne) Endocrinology Despite the wealth of information on biomarkers of diabetes complications in adults with type 1 diabetes, data in the pediatric population is limited. Diabetic nephropathy (DN), the leading cause of mortality in type 1 diabetes T1D), could be potentially missed in youth, as albuminuria, the current “gold” standard, may be transient and may not reflect permanent renal impairment. Soluble alpha KL has emerged as a potential marker of early diabetic nephropathy. Seventy-nine pediatric patients with type 1 diabetes meeting ISPAD criteria for nephropathy screening were consecutively recruited (90% Caucasian, 51% male, mean age 16.1 ± 3.1 years, duration of T1D 7.2 ± 3.9 years, 2-year average HbA1c 8.0 ± 1.3%, and serum and urine samples were collected for analysis. Serum Klotho (KL) and circulating miRNA levels of select miRNA involved in the pathogenesis of DN were estimated. KL had a strong inverse correlation with diabetes duration and HbA1c, two important risk factors in the development of diabetes complications. Serum miR-192 were negatively associated with KL among children with prolonged duration of diabetes (≥12 years) after adjustment for age and sex. In cell culture, overexpression of miR-192 significantly downregulated KL mRNA and protein levels, and reduced KL levels in the media. miR-192 mimic reduced luciferase activity in a reporter containing the KL 3’ UTR (60% compared to controls, p<0.01), and the inhibitor rescued it. Deletion of a potential binding site for miR-192 in the KL 3’UTR completely abolished the effect of miR-192 in the reporter assay, suggesting that KL is a direct target gene of miR-192. Overexpression of miR-192 significantly increased oxidative stress (MDA) and expression of inflammatory and senescence markers IL-6 and p16. Inhibition of miR-192 significantly reduced levels of MDA, IL-6 and p16. In summary, we demonstrate an increase in miR-192 and a decrease in KL levels in children with prolonged duration of T1D. We demonstrate a novel role for miR-192 in directly regulating KL levels, and through that, senescence and oxidative stress, key pathological processes in the development of DN. miR-192 and/or KL levels are altered with severity and duration of diabetes and could serve as early biomarkers for DN. Frontiers Media S.A. 2022-08-05 /pmc/articles/PMC9388782/ /pubmed/35992154 http://dx.doi.org/10.3389/fendo.2022.937093 Text en Copyright © 2022 Gong, Banchs, Liu, Fu, Arena, Forno, Libman, Ho and Muzumdar https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Endocrinology Gong, Zhenwei Banchs, Pedro A. Pagán Liu, Ye Fu, Haoyi Arena, Vincent C. Forno, Erick Libman, Ingrid Ho, Jacqueline Muzumdar, Radhika Serum α-KL, a potential early marker of diabetes complications in youth with T1D, is regulated by miRNA 192 |
title | Serum α-KL, a potential early marker of diabetes complications in youth with T1D, is regulated by miRNA 192 |
title_full | Serum α-KL, a potential early marker of diabetes complications in youth with T1D, is regulated by miRNA 192 |
title_fullStr | Serum α-KL, a potential early marker of diabetes complications in youth with T1D, is regulated by miRNA 192 |
title_full_unstemmed | Serum α-KL, a potential early marker of diabetes complications in youth with T1D, is regulated by miRNA 192 |
title_short | Serum α-KL, a potential early marker of diabetes complications in youth with T1D, is regulated by miRNA 192 |
title_sort | serum α-kl, a potential early marker of diabetes complications in youth with t1d, is regulated by mirna 192 |
topic | Endocrinology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9388782/ https://www.ncbi.nlm.nih.gov/pubmed/35992154 http://dx.doi.org/10.3389/fendo.2022.937093 |
work_keys_str_mv | AT gongzhenwei serumaklapotentialearlymarkerofdiabetescomplicationsinyouthwitht1disregulatedbymirna192 AT banchspedroapagan serumaklapotentialearlymarkerofdiabetescomplicationsinyouthwitht1disregulatedbymirna192 AT liuye serumaklapotentialearlymarkerofdiabetescomplicationsinyouthwitht1disregulatedbymirna192 AT fuhaoyi serumaklapotentialearlymarkerofdiabetescomplicationsinyouthwitht1disregulatedbymirna192 AT arenavincentc serumaklapotentialearlymarkerofdiabetescomplicationsinyouthwitht1disregulatedbymirna192 AT fornoerick serumaklapotentialearlymarkerofdiabetescomplicationsinyouthwitht1disregulatedbymirna192 AT libmaningrid serumaklapotentialearlymarkerofdiabetescomplicationsinyouthwitht1disregulatedbymirna192 AT hojacqueline serumaklapotentialearlymarkerofdiabetescomplicationsinyouthwitht1disregulatedbymirna192 AT muzumdarradhika serumaklapotentialearlymarkerofdiabetescomplicationsinyouthwitht1disregulatedbymirna192 |