Journal article
T-Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes
Diabetes, Vol.70(8), pp.1754-1766
2021
PMID: 34285121
Abstract
Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of diabetic kidney disease (DKD). In type 1 diabetes, increased urinary albumin-to-creatinine ratio (uACR) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule-1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk. DKD risk was assigned in youth with type 1 diabetes (n = 100; 20.0 ± 2.8 years; males/females, 54:46; HbA1c 66.1 [12.3] mmol/mol; diabetes duration 10.7 ± 5.2 years; and BMI 24.5 [5.3] kg/m2) and 10-year historical uACR, HbA1c, and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared with streptozotocin diabetes in apolipoprotein E−/− mice. Kidney biopsies were used to examine infiltration of KIM-1–expressing T cells in DKD and compared with other chronic kidney disease. Individuals at high risk for DKD had persistent elevations in uACR defined by area under the curve (AUC; uACRAUC0–10yrs, 29.7 ± 8.8 vs. 4.5 ± 0.5; P < 0.01 vs. low risk) and early kidney dysfunction, including ∼8.3 mL/min/1.73 m2 higher estimated glomerular filtration rates (modified Schwartz equation; Padj < 0.031 vs. low risk) and plasma KIM-1 concentrations (∼15% higher vs. low risk; P < 0.034). High-risk individuals had greater glycemic variability and increased peripheral blood T-cell KIM-1 expression, particularly on CD8+ T cells. These findings were confirmed in a murine model of glycemic variability both in the presence and absence of diabetes. KIM-1+ T cells were also infiltrating kidney biopsies from individuals with DKD. Healthy primary human proximal tubule epithelial cells exposed to plasma from high-risk youth with diabetes showed elevated collagen IV and sodium–glucose cotransporter 2 expression, alleviated with KIM-1 blockade. Taken together, these studies suggest that glycemic variations confer risk for DKD in diabetes via increased CD8+ T-cell production of KIM-1.
Details
- Title
- T-Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes
- Authors
- Josephine M Forbes (Corresponding Author) - University of QueenslandDomenica A McCarthy - Translational Research InstituteAndrew J Kassianos - University of QueenslandTracey Baskerville - University of QueenslandAmelia K Fotheringham - University of QueenslandKurt T K Giuliani - Royal Brisbane and Women's HospitalAnca Grivei - Queensland HealthAndrew J Murphy - Baker Heart and Diabetes InstituteMichelle C Flynn - Baker Heart and Diabetes InstituteMitchell A Sullivan - University of QueenslandPreeti Chandrashekar - University of QueenslandRani Whiddett - Mater ResearchKristen J Radford - University of QueenslandNicole Flemming - Mater ResearchSam S Beard - Translational Research InstituteNeisha D’Silva - Mater Health ServicesJanelle Nisbett - Mater Health ServicesAdam Morton - Mater Health ServicesStephanie Teasdale - Mater Health ServicesAnthony W Russell - University of QueenslandNicole M Isbel - Princess Alexandra HospitalTimothy William Jones - Telethon Kids InstituteJennifer Couper - University of AdelaideHelen G Healy - University of QueenslandMark Harris - Children’s Health Queensland Hospital and Health ServiceKim Donaghue - Children's Hospital at WestmeadDavid W Johnson - University of QueenslandAndrew Cotterill - Children’s Health Queensland Hospital and Health ServiceHelen L. Barrett - Mater Health ServicesTrisha O’Moore-Sullivan - Mater Health Services
- Additional notes
- This study was presented at the Australasian Diabetes Congress 2020, 11–13 November 2020.
- Publication details
- Diabetes, Vol.70(8), pp.1754-1766
- Publisher
- American Diabetes Association
- Date published
- 2021
- DOI
- 10.2337/db20-1081
- ISSN
- 1939-327X
- PMID
- 34285121
- Organisation Unit
- School of Health - Biomedicine
- Language
- English
- Record Identifier
- 991035094502621
- Output Type
- Journal article
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- Endocrinology & Metabolism
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Source: InCites