T-Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes

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.

A Comprehensive Analysis of HAVCR1 as a Prognostic and Diagnostic Marker for Pan-Cancer

“…HAVCR1 is a costimulatory molecule expressed on the surface of immune cells, which promotes activation and proliferation of immune cells, cytokine secretion and regulates the immune response ( Guo et al, 2019 ; Evans and Liu, 2020 ; Xiao et al, 2020 ). In this regard, HAVCR1 can alter the function of CD8 + T cells and NK cells for an effective antitumor immune response ( Lee et al, 2010 ; Forbes et al, 2021 ). An increasing body of evidence suggests that the positive and negative regulation of HAVCR1 by ligand-binding is essential for maintaining immune homeostasis ( Xiao et al, 2007 ; Brooks et al, 2015 ; Du et al, 2016 ).…”

The Role of Immune Cells in DKD: Mechanisms and Targeted Therapies

“…Glycemic changes increase KIM-1 production from CD8 + T cells, thus raising the risk of DKD in patients with diabetes. 68 Increased numbers of peripheral blood CD4 + CR5 + PD-1 + THF cells were also found in patients with DKD, 69 and patients with type 2 diabetes and proteinuria express more CD25 and CD69 on their circulating CD8 + T cells. 70 Moreover, the serum levels of T-lymphocyte activation markers, specifically CD28 and CTLA-4, increase as DKD progresses.…”

T cells and their products in diabetic kidney disease

“…KIM-1 is also known as T-cell lg mucin 1 (TIM-1) or hepatitis A virus cellular receptor 1 and has been reported as a transmembrane glycoprotein receptor on T cells ( 120 ). Recent studies have revealed elevations in KIM-1, suggesting that glycemic variations may increase the production of KIM-1 in CD8 + T cells in individuals with DKD, thereby increasing the risk of DKD ( 121 ). The elevations in circulating KIM-1 also increases the urinary KIM-1 in DN, verifying that KIM-1 can be a biomarker and a reliable predictor of diabetic kidney injury ( 122 ).…”