Role and Association of Inflammatory and Apoptotic Caspases in Renal Tubulointerstitial Fibrosis

Abstract

Background/Aims: Caspases, an evolutionary conserved family of aspartate-specific cystein proteases, play pivotal roles in apoptotic and inflammatory signaling. Thus far, 14 mammalian caspases are identified and categorized into 3 distinct sub-types: inflammatory caspases, apoptotic initiator and apoptotic executioner. Caspase-1 is an inflammatory caspase, while caspase-7 belongs to apoptotic executioner. The roles and association of these two distinct types of caspases in renal tubulointerstitial fibrosis (TIF) have not been well recognized. Methods: Caspase-1 inhibitor Z-YVAD-FMK and caspase-7 siRNA were used in tubular epithelial cell line NRK-52E (TECs) to test their effects on transforming growth factor-beta1 (TGF-β1) stimulation. In vivo, Unilateral ureteral obstruction (UUO) animal model was employed in wild-type (WT) and caspase-1 knock out (KO) (caspase-1^-/-) mice. Results: In current study, we found that caspase-7 was obviously activated in cultured TECs stimulated by TGF-β1 and in UUO model of WT mice. While in UUO model of caspase-1 KO mice, the increased caspase-7 activation was suppressed significantly along with reduced trans-differentiation and minimized extracellular matrix (ECM) accumulation, as demonstrated by western blot, Masson trichrome staining and immunohistochemistry. In addition, pharmacological inhibition of caspase-1 dampened caspase-7 activation and TECs' transdifferentiation induced by TGF-β1 exposure, which was consistent with in vivo study. Notably, caspase-7 gene knock down by specific siRNA abrogated TGF-β1 driven TECs' trans-differentiation and reduced ECM accumulation. Conclusions: Our study associated inflammatory and apoptotic caspases in TIF for the first time and we further confirmed that caspase-1 activation is an upstream event of apoptotic caspase-7 induction in TIF triggered by UUO and in TECs mediated by TGF-β1 induced transdifferentiation.

LAMP3 plays an oncogenic role in osteosarcoma cells partially by inhibiting TP53

“…Caspase-1 is an inflammatory caspase. Once activated, its downstream executioner caspases can be induced, which is pivotal to induce apoptosis [ 23 ]. ABL1 is a proto-oncogene encoding tyrosine kinase.…”

Apoptosis and its therapeutic implications in neurodegenerative diseases

“…However, they can be activated upon their cleavage subsequent to their dimerization, which is triggered by various adapter proteins that bind to specific sites in the procaspase (Kim et al, 2014; Marek, 2013; Parrish et al, 2013). Caspases are categorized into inflammatory caspases (caspases 1, 4, 5, and 12) and apoptotic caspases (Ke et al, 2016; McIlwain et al, 2013). Based on their mechanism of action and their position in the apoptotic signaling pathways, apoptotic caspases are subdivided into initiator caspases (caspase 2, 8, 9, and 10) and executioner or effector caspases (caspases 3, 6, and 7) (Boice & Bouchier‐Hayes, 2020; Erekat, 2018a; Wang, Hu, et al, 2020).…”

Nuclear factor E2-related factor-2 (Nrf2) regulates renal tubulointerstitial fibrosis and Gasdermin D-driven pyroptosis induced by high glucose in HK-2 cells via Caspase-1

“…The NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) in ammasome is an intracellular complex that activates caspase-1, which then cleaves the gasdermin (GSDM) family proteins, leading to pyroptosis. Ke et al reported that transdifferentiation was reduced and extracellular matrix accumulation was minimized in the UUO model of caspase-1 KO mice, and pharmacological inhibition of caspase-1 dampened tubular epithelial cell line NRK-52Es' transdifferentiation induced by TGF-β1 exposure [10].…”