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.