P16^INK4a played a critical role in exacerbating acute tubular necrosis in acute kidney injury.

Abstract

Acute kidney injury (AKI) is a common clinical syndrome with high morbidity and mortality, which is mostly caused by acute tubular necrosis (ATN). AKI is associated with many factors, including cell senescence, inflammatory infiltration, apoptosis and excessive accumulation of reactive oxygen species (ROS). P16^INK4a (hereafter termed p16) inhibits cell cycle, and the absence of <i>p16</i> can significantly slow the progression of cell senescence. We found that the expression of p16 was significantly increased after ATN. To determine whether p16 could exacerbate ATN degree and whether <i>p16</i> deletion had protective effects against the ATN and renal dysfunction in AKI progression, glycerol-rhabdomyolysis-induced ATN was performed in eight-week-old <i>p16</i> knockout and wild-type (WT) littermates. Their ATN phenotypes were analyzed; the levels of serum creatinine and serum urea nitrogen were detected; inflammation, cell apoptosis, ROS level and ROS signaling pathway molecules were examined using histopathological and molecular techniques. We found that compared to WT mice, <i>p16</i> deletion has protective effects against the ATN phenotype and renal dysfunction in AKI progression through ameliorating inflammatory infiltration and proinflammatory factor expression by inhibiting NF-κB proinflammatory pathway, decreasing cell apoptosis by balancing the expressions between pro-apoptotic and anti-apoptotic molecules, and reducing ROS levels and downregulating ROS signaling pathway molecules including AIF, PGAM5 and KEAP1. Thus, <i>p16</i> deletion or inhibition and p16 positive cell clearance would be a novel strategy for preventing ATN in AKI progression.