T Cells Mediate Kidney Tubular Injury via Impaired PDHA1 and Autophagy in Type 1 Diabetes.
J Clin Endocrinol Metab
; 107(9): 2556-2570, 2022 08 18.
Article
em En
| MEDLINE
| ID: mdl-35731579
ABSTRACT
CONTEXT Nephropathy is a severe complication of type 1 diabetes (T1DM). However, the interaction between the PDHA1-regulated mechanism and CD4+â
T cells in the early stage of kidney tubular injury remains unknown. OBJECTIVE:
To evaluate the role of PDHA1 in the regulation of tubular cells and CD4+â T cells and further to study its interaction in tubular cell injury in T1DM.METHODS:
Plasma and total RNA were collected from T cells of T1DM patients (nâ =â 35) and healthy donors (nâ =â 33) and evaluated for neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1, PDHA1, and biomarkers of CD4+â T cells including T helper 1 cells (Th1) and regulatory T cells (Treg) markers. HK-2 cells cocultured with CD4+â T cells from T1DM patients or healthy donors (HDs) to evaluate the interaction with CD4+â T cells.RESULTS:
Increased PDHA1 gene expression levels in CD4+â T cells were positively associated with the plasma level of NGAL in T1DM patients and HDs. Our data demonstrated that the Th1/Treg subsets skewed Th1 in T1DM. Knockdown of PDHA1 in kidney tubular cells decreased ATP/ROS production, NAD/NADH ratio, mitochondrial respiration, and cell apoptosis. Furthermore, PDHA1 depletion induced impaired autophagic flux. Coculture of tubular cells and T1DM T cells showed impaired CPT1A, upregulated FASN, and induced kidney injury.CONCLUSION:
Our findings indicate that Th1 cells induced tubular cell injury through dysregulated metabolic reprogramming and autophagy, thereby indicating a new therapeutic approach for kidney tubular injury in T1DM.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Diabetes Mellitus Tipo 1
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article