Pyroptosis in renal inflammation and fibrosis: current knowledge and clinical significance

Abstract

Pyroptosis is a novel inflammatory form of regulated cell death (RCD), characterized by cell swelling, membrane rupture, and pro-inflammatory effects. It is recognized as a potent inflammatory response required for maintaining organismal homeostasis. However, excessive and persistent pyroptosis contributes to severe inflammatory responses and accelerates the progression of numerous inflammation-related disorders. In pyroptosis, activated inflammasomes cleave gasdermins (GSDMs) and generate membrane holes, releasing interleukin (IL)-1β/18, ultimately causing pyroptotic cell death. Mechanistically, pyroptosis is categorized into caspase-1-mediated classical pyroptotic pathway and caspase-4/5/11-mediated non-classical pyroptotic pathway. Renal fibrosis is a kidney disease characterized by the loss of structural and functional units, the proliferation of fibroblasts and myofibroblasts, and extracellular matrix (ECM) accumulation, which leads to interstitial fibrosis of the kidney tubules. Histologically, renal fibrosis is the terminal stage of chronic inflammatory kidney disease. Although there is a multitude of newly discovered information regarding pyroptosis, the regulatory roles of pyroptosis involved in renal fibrosis still need to be fully comprehended, and how to improve clinical outcomes remains obscure. Hence, this review systematically summarizes the novel findings regarding the role of pyroptosis in the pathogenesis of renal fibrosis and discusses potential biomarkers and drugs for anti-fibrotic therapeutic strategies.

Podocyte injury and death: New insights into lupus nephritis pathogenesis and therapy

“…Podocyte death is induced by multiple factors. Among canonical programmed cell death pathways, apoptosis stands out as the predominant type, although it occasionally intersects with others, notably necroptosis and pyroptosis 92,111,112 . Both necroptosis and pyroptosis are inflammation‐inducible pathways that feature a loss of plasma integrity and are characterized by a cascade of signals including MLKL and inflammasome activation, respectively 71 .…”

“…Among canonical programmed cell death pathways, apoptosis stands out as the predominant type, although it occasionally intersects with others, notably necroptosis and pyroptosis. 92,111,112 Both necroptosis and pyroptosis are inflammation-inducible pathways that feature a loss of plasma integrity and are characterized by a cascade of signals including MLKL and inflammasome activation, respectively. 71 Additionally, in the absence of concrete evidence regarding the occurrence of ferroptosis in LN podocytes, additional findings are needed to conclusively understand podocyte dysfunction in LN.…”

Renal macrophages and NLRP3 inflammasomes in kidney diseases and therapeutics

“…Studies on GSDMD-deficient mice indicate heightened vulnerability to injury in both IRI and cisplatin-induced acute kidney injury (AKI) models. Conversely, other research suggests that either genetic deficiency of GSDMD or inhibition of the NLRP3 inflammasome might offer protection in AKI models [ 173 , 174 , 177 ]. Importantly, despite in vivo data post-IRI and single-cell analysis, GSDMD expression hasn’t been observed in tubular epithelial cells following murine kidney IRI [ 176 , 178 ].…”

Deeper insight into ferroptosis: association with Alzheimer’s, Parkinson’s disease, and brain tumors and their possible treatment by nanomaterials induced ferroptosis

“…A number of recent studies reported NMs-assisted GBS therapy for instance ferroptosis, gene therapy (GT) [ 266 , 273 ], radiotherapy [ 274 ], photothermal therapy (PTT) [ 275 ], magnetothermal therapy [ 276 , 277 ], and immunotherapy [ 278 ]. Ferroptosis is an iron-mediated apoptosis distinguished from necrosis, autophagy [ 279 ], apoptosis, and pyroptosis [ 280 ]. Excess amount of iron reacts with H 2 O 2 and generates free radicals and singlet O 2 in cells.…”