Acute kidney injury (AKI) complicates at least 5% of all hospitalizations and up to 30% of cardiac surgeries, increasing mortality and progressing to chronic renal disease in a significant number of patients. Ischemia- reperfusion injury (IRI) is a major pathogenic factor in the development of AKI. Inflammation contributes significantly to the loss of renal function and kidney cell death. CD4+FoxP3+ regulatory T cells (Tregs) are renal-protective lymphocytes that raise the threshold of experimental AKI (i.e. mice with reduced Treg numbers are highly susceptible to short ischemic times). In addition, augmenting Treg numbers by IV injection (adoptive transfer) of isolated Tregs to nave mice prior to severe kidney IRI offers marked protection from injury and dysfunction. Our investigation into the mechanism of action for Tregs has revealed that expression of both the cytokine interleukin 10 (IL-10) and the cell surface protein programmed death 1 (PD-1) by Tregs are required. IL-10 suppresses trafficking and inflammatory mediator production by myeloid immune cells through binding the IL-10 receptor (IL-10R). The consequences of PD-1 on Tregs binding with its ligand PD-L1 expressed on other cells are not currently known. Information from the literature and from our own studies suggest that PD-1 activation would enhance oxidative phosphorylation, CD25 (an important cell surface receptor that promotes Treg function and survival) and IL-10 expression in Tregs. These intracellular consequences of PD-1 activation and their role in protection from kidney IRI will be determined using mouse and human Tregs in Aim 1. Preliminary data demonstrate that antibody-mediated blockade of PD-L1 or the IL-10R in recipient mice, prior to Treg adoptive transfer, negates their protective action in IRI. The cells that must express PD-L1 and the IL-10R to interact with and respond to Tregs and protect the kidney are not known. PD-L1 is expressed on kidney vascular endothelial cells and our preliminary data reveal preferential intraluminal Treg accumulation in the peritubular vasculature during reperfusion. We hypothesize that Treg-mediated protection from AKI requires the expression of PD-L1 on endothelial cells that line the inside of blood vessels, and the IL-10 receptor on myeloid immune cells. We will use mouse models that lack PD-L1 (Aim 2) or the IL-10R (Aim 3) in vascular endothelial cells and myeloid immune cells, respectively, to zero in on the cells interact with Tregs and respond to IL-10 produced by Tregs in a way that is protective to the kidney. These mechanistic studies in mice will provide a platform for future pre-clinical and clinical studies of the therapeutic utility of Tregs and Treg-associated mechanisms in AKI.

Public Health Relevance

Acute kidney injury is a major problem for hospitalized patients, which is costly in terms of length of hospital stay, mortality and financial burden on th healthcare system. Inflammation is a pathogenic factor in acute kidney injury and pre-clinical studies have revealed that anti-inflammatory cells called regulatory T cells protect the kidney from injury. Exploring kidney-protective pathways involving regulatory T cells in mice and humans will reveal new therapeutic targets to prevent, or speed recovery from acute kidney injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK104963-04
Application #
9621386
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Chan, Kevin E
Project Start
2015-12-15
Project End
2020-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Stremska, Marta E; Jose, Sheethal; Sabapathy, Vikram et al. (2017) IL233, A Novel IL-2 and IL-33 Hybrid Cytokine, Ameliorates Renal Injury. J Am Soc Nephrol 28:2681-2693
Sharma, Rahul; Kinsey, Gilbert R (2017) Regulatory T cells in Acute and Chronic Kidney Diseases. Am J Physiol Renal Physiol :ajprenal.00236.2017