Abstract
Excessive deposition of extracellular matrix proteins in renal tissues causes renal fibrosis and renal function failure. Mammalian cells primarily use the autophagy-lysosome system to degrade misfolded/aggregated proteins and dysfunctional organelles. MAP1S is an autophagy activator and promotes the biogenesis and degradation of autophagosomes. Previously, we reported that MAP1S suppresses hepatocellular carcinogenesis in a mouse model and predicts a better prognosis in patients suffering from clear cell renal cell carcinomas. Furthermore, we have characterized that MAP1S enhances the turnover of fibronectin, and mice overexpressing LC3 but with MAP1S deleted accumulate fibronectin and develop liver fibrosis because of the synergistic impact of LC3-induced over-synthesis of fibronectin and MAP1S depletion-caused impairment of fibronectin degradation. Here we show that a suppression of MAP1S in renal cells caused an impairment of autophagy clearance of fibronectin and an activation of pyroptosis. Depletion of MAP1S in mice leads to an accumulation of fibrosis-related proteins and the development of renal fibrosis in aged mice. The levels of MAP1S were dramatically reduced and levels of fibronectin were greatly elevated in renal fibrotic tissues from patients diagnosed as renal atrophy and renal failure. Therefore, MAP1S deficiency may cause the accumulation of fibronectin and the development of renal fibrosis.
Highlights
Mammalian cells primarily use the autophagy-lysosome pathway to degrade dysfunctional organelles, misfolded/aggregated proteins and other macromolecules [1]
Six patients diagnosed as renal atrophy and renal failure and six normal controls were subjected to analyses of renal fibrosis by H&E staining
High levels of fibronectin are associated with low levels of MAP1S in patients suffering from renal fibrosis
Summary
Mammalian cells primarily use the autophagy-lysosome pathway to degrade dysfunctional organelles, misfolded/aggregated proteins and other macromolecules [1]. Autophagy defects lead to impairment of fibronectin degradation and excessive deposition of fibronectin as extracellular matrix, which leads to renal fibrosis [6]. Autophagy defects lead to enhancement of oxidative stresses [1, 7]. The activation of caspase-1 subsequently induces secretion of potent proinflammatory cytokines interleukin-1β (IL-1β) and IL18, mitochondrial dysfunction, production of excess reactive oxygen species, and eventually an inflammatory form of cell death referred as pyroptosis [9,10,11,12,13,14]. Inflammation-induced renal tissue remodeling promotes the production of fibronectin to boost renal fibrosis [16, 17]
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