3.3 Necroptosis in kidney fibrosis
Fibrosis, characterized by loss of capillary networks, excessive deposition of fibrillary collagens, activated myofibroblasts and inflammatory cells (Zeisberg et al. 2003, Humphreys et al. 2010), is the eventual common pathway of chronic kidney disease (CKD) (Brosius et al. 2009). Present studies have shown that necroptosis signal responses are widely exist in various acute and chronic kidney diseases caused by different reasons including I/R (Linkermann et al. 2013a, Linkermann et al. 2012), cisplatin-based chemotherapy or radiocontrast (Linkermann et al. 2013b, Xu et al. 2015) and unilateral nephrectomy(Zhu et al. 2015). Evidence show that RIPK1and RIPK3 deficiency in kidney I/R injury can improve systemic inflammation associated with A20 deficiency or high-dose TNF model, which is consistent with necroptosis-independent functions for RIPK1 and RIPK3 (Newton et al. 2016). Ying Shi et al found that RIPK3 can mediate renal fibrogenesis by the domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. Diabetic RIPK3-/- mice and RIPK3 inhibitor dabrafenib can obviously reduce collagen deposition and myofibroblast activation in kidney (Shi et al. 2020b). Moreover, increased expression and interactions between RIPK3 and MLKL induced necroptosis of renal proximal tubular cells under the conditions of renal I/R injury. Gene deletion of RIPK3 or MLKL improved renal tubular cell necroptosis, macrophage infiltration and NLRP3 inflammasome activation with a reduction in caspase-1 activation and maturation of IL-1β, and then eventually decreased interstitial fibrogenesis in the long term after IRI. These studies indicate that necroinflammation activate by RIPK3-MLKL-dependent necroptosis plays an important role in the progression of IRI to CKD (Chen et al. 2018a). In clinical studies, researchers also found that in human oxalate crystal-related AKI, dying tubular cells stain positive for p-MLKL. Deficiency of RIPK3 or MLKL prevents oxalate crystal-induced AKI. The inhibitor of human MLKL (Nec-1 and necrosulfonamide) can suppress crystal-induced cell death in human renal progenitor cells (Mulay et al. 2016). The above studies indicate that inhibit the key proteins of necroptosis may be a potential target for the treatment of acute and chronic kidney disease.