학술논문
T Cells Mediate Kidney Tubular Injury via Impaired PDHA1 and Autophagy in Type 1 Diabetes
Clinical Research Article
Clinical Research Article
Document Type
Report
Author
Source
Journal of Clinical Endocrinology & Metabolism. September 2022, Vol. 107 Issue 9, p2556, 15 p.
Subject
Language
English
ISSN
0021-972X
Abstract
The emergence of nephropathy is the most severe complication of type 1 diabetes (T1DM) because it is mainly incurable once kidney cells are injured (1). In the majority of individuals [...]
Context: Nephropathy is a severe complication of type 1 diabetes (T1DM). However, the interaction between the PDHA1-regulated mechanism and CD[4.sup.+] 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 CD[4.sup.+] 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 (n = 35) and healthy donors (n = 33) and evaluated for neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1, PDHA1, and biomarkers of CD[4.sup.+] T cells including T helper 1 cells (Th1) and regulatory T cells (Treg) markers. HK-2 cells cocultured with CD[4.sup.+] T cells from T1DM patients or healthy donors (HDs) to evaluate the interaction with CD[4.sup.+] T cells. Results: Increased PDHA1 gene expression levels in CD[4.sup.+] 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. Key Words: PDHA1, NGAL, Th 1 cells, kidney tubular injury, type 1 diabetes Abbreviations: AKI, acute kidney injury; BMI, body mass index; CPT1A, carnitine palmitoyltransferase 1A; DKD, diabetic kidney disease; FAO, fatty acid oxidation; FAS, fatty acid synthesis; FASN, fatty acid synthase; GFR, glomerular filtration rate; HD, healthy donor; HG, high glucose; KIM-1, kidney injury molecule-1; NG, normal glucose; NGAL, neutrophil gelatinase-associated lipocalin; OCR, oxygen consumption rate; PDHA1, pyruvate dehydrogenase alpha 1; qPCR, quantitative PCR; T1DM, type 1 diabetes mellitus; Th1, T helper 1 cells; Treg, Regulatory T cells; ROS, reactive oxygen species; STAT4, Signal transducers and activators of transcription 4
Context: Nephropathy is a severe complication of type 1 diabetes (T1DM). However, the interaction between the PDHA1-regulated mechanism and CD[4.sup.+] 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 CD[4.sup.+] 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 (n = 35) and healthy donors (n = 33) and evaluated for neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1, PDHA1, and biomarkers of CD[4.sup.+] T cells including T helper 1 cells (Th1) and regulatory T cells (Treg) markers. HK-2 cells cocultured with CD[4.sup.+] T cells from T1DM patients or healthy donors (HDs) to evaluate the interaction with CD[4.sup.+] T cells. Results: Increased PDHA1 gene expression levels in CD[4.sup.+] 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. Key Words: PDHA1, NGAL, Th 1 cells, kidney tubular injury, type 1 diabetes Abbreviations: AKI, acute kidney injury; BMI, body mass index; CPT1A, carnitine palmitoyltransferase 1A; DKD, diabetic kidney disease; FAO, fatty acid oxidation; FAS, fatty acid synthesis; FASN, fatty acid synthase; GFR, glomerular filtration rate; HD, healthy donor; HG, high glucose; KIM-1, kidney injury molecule-1; NG, normal glucose; NGAL, neutrophil gelatinase-associated lipocalin; OCR, oxygen consumption rate; PDHA1, pyruvate dehydrogenase alpha 1; qPCR, quantitative PCR; T1DM, type 1 diabetes mellitus; Th1, T helper 1 cells; Treg, Regulatory T cells; ROS, reactive oxygen species; STAT4, Signal transducers and activators of transcription 4