SECRETORY LEUKOCYTE PROTEINASE INHIBITOR PROTECTS ACUTE KIDNEY INJURY THROUGH IMMUNE AND NON-IMMUNE PATHWAYS

GUERRIERI D, AMBROSI N, ROMEO H, SALABERRY J,TONIOLO F, REMOLINS C, INCARDONA C, CASADEI D, CHULUYAN H

SHOCK

LIPPINCOTT WILLIAMS & WILKINS

Lugar: Philadelphia; Año: 2021 vol. 56 p. 1019 - 1027

1073-2322

Acute kidney injury (AKI) is characterized by rapid loss of excretory function and is the clinical manifestation ofseveral disorders affecting the kidney. The aim of the present study was to investigate the mechanism of action of SecretoryLeukocyte Proteinase Inhibitor (SLPI) that protects the kidneys form AKI. In vivo and in vitro experiments were performed toassess the effect of SLPI on kidney injury. Animal models of kidney injury was generated by 40 min obstruction of kidney arteryand vein (ischemia-reperfusion injury model) or daily administration of 60 mg/kg/day of gentamicine for 5 day (gentamicin-associated AKI model). For in vitro assessment, human renal epithelium HK-2 cells were cultured under serum starvationconditions or with tacrolimus. The administration of SLPI (250 mg/kg, i.p.) reduced elevated plasma creatinine and blood ureanitrogen levels, tissue myeloperoxidase content, and acute tubular necrosis induced by kidney damage. Furthermore, SLPItreatment reduced CD86, CD68, CD14, CCL2, TNFa, and IL-10 transcripts in kidney biopsies. To further analyze a direct effectof SLPI on renal epithelial cells, HK-2 cells from human renal epithelium were cultured under serum starvation conditions or withtacrolimus. Both conditions induced apoptosis of HK-2 cells which was reduced when SLPI was present in the culture medium.Furthermore, SLPI favored the proliferation and migration of HK-2 cells. An analysis of the gene profiles of HK-2 cells treatedwith calcineurin inhibitors affected inflammatory and non-inflammatory pathways that were reversed by SLPI. Among them,SLPI down modulated the expression of CCL2, SLC5A3, and BECN1 but up-regulated the expression of TLR4, ATF4, ATF6,HSP90B, BBC3 SLC2A1, and TNFRSF10B. Overall, these results suggest that SLPI, in addition to its activity on immune cells,may directly target tubular epithelial cells of the kidney to mediate the nephroprotective activity in AKI.