Background
Acute kidney injury frequently results from acute cardiac dysfunction and is called acute cardiorenal syndrome. We assessed the role of natural killer T-cells (NKT) in acute cardiorenal syndrome.
Methods
We modeled acute cardiorenal syndrome by performing cardiac arrest and cardiopulmonary resuscitation (CA/CPR) in mice. CA was induced by intravenous potassium chloride injection in intubated and anesthetized mice. After 8 minutes CPR was performed with epinephrine and chest compressions. Kidney T-cells were assessed with flow cytometry. NKT cells were depleted with intravenous injection of anti-NK1.1 antibody. Kidney function was quantified 24 hours after CA/CPR through glomerular filtration rate (GFR) and urine output. Kidney NKT cells from sham and CA/CPR animals were isolated via fluorescence activated sorting 24 hours after CA/CPR then profiled with single cell RNA sequencing. CD1d expression in mouse and human kidneys was assessed with flow cytometry and immunofluorescence. Gentamicin was used to injure human proximal tubule cells in vitro.
Results
NKT cells constituted 33% of mouse kidney T-cells at baseline. NK1.1 antibody administration caused 95% depletion of kidney NK cells and 80% depletion of NKT cells. NK1.1 antibody administration also resulted in increased GFR and urine output 24 hours after CA/CPR compared to vehicle treatment. After CA/CPR there was substantially increased kidney CD1d expression, almost exclusively in proximal tubule epithelial cells. CD1d protein expression was detected in human proximal tubule cells from brain-dead donor kidneys using flow cytometry. Gentamicin resulted in increased CD1d expression in human proximal tubule cells in vitro. Single cell RNA sequencing of mouse NKT cells revealed increased expression of transcripts associated with cytotoxicity, such as those coding for killer lectin receptors and Fas ligand, after CA/CPR.
Conclusions
NKT cells are abundant in the kidney and may play a role in acute cardiorenal syndrome. Further studies are needed to determine the role of proximal tubule antigen presentation and NKT cytotoxicity in kidney injury.