Pathophysiological role of different tubular epithelial cell death modes in acute kidney injury

Abstract

The histological substrate of many forms of intrinsic acute kidney injury (AKI) has been classically attributed to tubular necrosis. However, more recent studies indicate that necrosis is not the main form of cell death in AKI and that other forms such as apoptosis, regulated necrosis (i.e. necroptosis and parthanatos), autophagic cell death and mitotic catastrophe, also participate in AKI and that their contribution depends on the cause and stage of AKI. Herein, we briefly summarize the main characteristics of the major types of cell death and we also critically review the existing evidence on the occurrence of different types of cell death reported in the most common experimental models of AKI and human specimens. We also discuss the pathophysiological mechanisms linking tubule epithelial cell death with reduced glomerular filtration, azotaemia and hydroelectrolytic imbalance. For instance, special relevance is given to the analysis of the inflammatory component of some forms of cell death over that of others, as an important and differential pathophysiological determinant. Finally, known molecular mechanisms and signalling pathways involved in each cell death type pose appropriate targets to specifically prevent or reverse AKI, provided that further knowledge of their participation and repercussion in each AKI syndrome is progressively increased in the near future.

Ferroptosis: Death by Lipid Peroxidation

“…When liprostatin-1 was administered to mice with inducible loss of Gpx4 protein, it delayed the acute renal failure caused by Gpx4 depletion, and extended survival of mice compared to a vehicle-treated group [15]. These results reinforce the susceptibility of kidney tissue to ferroptosis and suggest the value of ferroptosis inhibitors to ameliorate kidney injury [59]. …”

Thioredoxin‐Interacting Protein Mediates NLRP3 Inflammasome Activation Involved in the Susceptibility to Ischemic Acute Kidney Injury in Diabetes

“…It is estimated that 1-2% of new hospital admissions and 2–7% of cases acquired during hospital stays are due to acute kidney injury (AKI) [1]. The major risk factors for AKI include diabetes mellitus (DM), hypertension, and congestive heart failure [2].…”

Expression and Function of Interleukin-1β-Induced Neutrophil Gelatinase-Associated Lipocalin in Renal Tubular Cells

“…Interleukin-1 (IL-1) family members such as IL-1β and IL-18 are associated with the development and progression of AKI [6–8]. IL-1β is initially synthesized as the inactive precursor pro-IL-1β, whose maturation is achieved through inflammasomes and caspase-1 [9,10].…”

“…Inflammasomes are protein assemblies in the cytoplasm that consist of three main components: a sensor protein (receptor), an adaptor protein, and caspase-1 [11]. They mediate the activation of a highly inflammatory form of cell death, pyroptosis [8,10]. In renal tubular cells, inflammasome-mediated caspase-1 activation and IL-1β generation are induced by several extra- and intracellular stimuli such as ischemic-reperfusion injury, adenosine triphosphate (ATP), hypotonic stress, uric acid crystals, mitochondrial dysfunction, and lysosomal rupture [11–14].…”