Regulated cell death pathways in kidney disease

• Published in: Nature reviews. Nephrology 2023-05, Vol.19 (5), p.281-299
• Main Authors: Sanz, Ana B., Sanchez-Niño, Maria Dolores, Ramos, Adrian M., Ortiz, Alberto
• Format: Article
• Language: English
• Subjects: 631/80/82/23; 692/4022/1585/4; Acute Kidney Injury - metabolism; Apoptosis; Apoptosis - physiology; Cell death; Ferroptosis; Humans; Kidney - metabolism; Kidney cancer; Kidney diseases; Medicine; Medicine & Public Health; Necrosis - metabolism; Necrosis - pathology; Nephrology; Pathogenesis; Review; Review Article
• ISSN: 1759-5061; 1759-507X; 1759-507X
• DOI: 10.1038/s41581-023-00694-0

Disorders of cell number that result from an imbalance between the death of parenchymal cells and the proliferation or recruitment of maladaptive cells contributes to the pathogenesis of kidney disease. Acute kidney injury can result from an acute loss of kidney epithelial cells. In chronic kidney disease, loss of kidney epithelial cells leads to glomerulosclerosis and tubular atrophy, whereas interstitial inflammation and fibrosis result from an excess of leukocytes and myofibroblasts. Other conditions, such as acquired cystic disease and kidney cancer, are characterized by excess numbers of cyst wall and malignant cells, respectively. Cell death modalities act to clear unwanted cells, but disproportionate responses can contribute to the detrimental loss of kidney cells. Indeed, pathways of regulated cell death — including apoptosis and necrosis — have emerged as central events in the pathogenesis of various kidney diseases that may be amenable to therapeutic intervention. Modes of regulated necrosis, such as ferroptosis, necroptosis and pyroptosis may cause kidney injury directly or through the recruitment of immune cells and stimulation of inflammatory responses. Importantly, multiple layers of interconnections exist between different modalities of regulated cell death, including shared triggers, molecular components and protective mechanisms. Pathways of regulated cell death may contribute to the pathogenesis of various kidney diseases. Here, the authors provide an overview of the relationship between necroptosis, pyroptosis, ferroptosis and apoptosis, the evidence supporting a role for these regulated pathways of necrosis in kidney disease, strategies for therapeutic targeting and research needs. Key points Regulated cell death through either apoptosis or necrosis contributes to parenchymal cell loss in acute and chronic kidney disease and may also modulate inflammation, fibrosis and the immune response. Therapeutic strategies that modulate apoptosis may interfere with or promote regulated necrosis. Available evidence in general supports a therapeutic benefit of targeting ferroptosis or necroptosis in preclinical models of kidney disease; however, the impact of targeting pyroptosis is less clear. The diverse forms of regulated necrosis may be interrelated, share molecular pathways and cell defence mechanisms and coexist in the same kidney disease, affecting different cell types or the same cell type synchronously or sequentially. Regulated necrosis ma