Natural Killer Lymphocytes Mediate Renal Fibrosis Due to Acute Cardiorenal Syndrome.

Key Points: Natural killer cells infiltrate the kidney after cardiac arrest and medial renal fibrosis. Granzyme A is produced by natural killer cells and causes mesenchymal cell expansion and fibrosis in type 1 cardiorenal syndrome.

Background: The AKI to CKD transition presents an opportunity for intervention to prevent CKD. Our laboratory developed a novel murine model of AKI-CKD transition and cardiac arrest/cardiopulmonary resuscitation (CA/CPR), in which all animals develop CKD at 7 weeks. The purpose of this study was to identify potential immune drivers of fibrosis after CA/CPR.

Methods: Cardiac arrest was induced by potassium chloride, and mice were resuscitated with chest compressions and epinephrine. The kidney immune landscape after CA/CPR was profiled using 11-color flow cytometry analysis and immunofluorescence. Immune cell-derived mediators of fibrosis were identified by analyzing data from three previously published single-cell or single-nuclear RNA sequencing studies. NRK49F fibroblasts were treated with granzyme A (GzA) , and then cell proliferation was quantified using 5-ethynyl-2′-deoxyuridine. GzA was pharmacologically inhibited both and .

Results: Immune cells infiltrated the kidney after CA/CPR, consisting primarily of innate immune cells, including monocytes/macrophages, neutrophils, and natural killer (NK) cells. NK cell infiltration immediately preceded mesenchymal cell expansion, which occurred starting 7 days after CA/CPR. Immune cells colocalized with mesenchymal cells, accumulating in the areas of fibrosis. Analysis of previously published single-cell or single-nuclear RNA sequencing data revealed GzA as a potential mediator of immune to mesenchymal communication. GzA administration to fibroblasts induced cell growth and proliferation. Pharmacologic blockade of GzA signaling attenuated fibrosis and improved renal function after CA/CPR.

Conclusions: Renal inflammation occurs during cardiorenal syndrome, which correlates with mesenchymal cell expansion. GzA, produced by NK cells, presents a novel therapeutic target to prevent the transition to CKD after AKI.