Fabry disease exacerbates renal interstitial fibrosis after unilateral ureteral obstruction via impaired autophagy and enhanced apoptosis

Abstract

Background Fabry disease is a rare X-linked genetic lysosomal disorder caused by mutations in the GLA gene encoding alpha-galactosidase A. Despite some data showing that profibrotic and proinflammatory cytokines and oxidative stress could be involved in Fabry disease-related renal injury, the pathogenic link between metabolic derangement within cells and renal injury remains unclear. Methods Renal fibrosis was triggered by unilateral ureteral obstruction (UUO) in mice with Fabry disease to investigate the pathogenic mechanism leading to fibrosis in diseased kidneys. Results Compared to kidneys of wild-type mice, lamellar inclusion bodies were recognized in proximal tubules of mice with Fabry disease. Sirius red and trichrome staining revealed significantly increased fibrosis in all UUO kidneys, though it was more prominent in obstructed Fabry kidneys. Renal messenger RNA levels of inflammatory cytokines and profibrotic factors were increased in all UUO kidneys compared to sham-operated kidneys but were not significantly different between UUO control and UUO Fabry mice. Protein levels of Nox2, Nox4, NQO1, catalase, SOD1, SOD2, and Nrf2 were not significantly different between UUO control and UUO Fabry kidneys, while the protein contents of LC3-II and LC3-I and expression of Beclin1 were significantly decreased in UUO kidneys of Fabry disease mouse models compared with wild-type mice. Notably, TUNEL-positive cells were elevated in obstructed kidneys of Fabry disease mice compared to wild-type control and UUO mice. Conclusion These findings suggest that impaired autophagy and enhanced apoptosis are probable mechanisms involved in enhanced renal fibrosis under the stimulus of UUO in Fabry disease.

Protective Effects of Carnosol on Renal Interstitial Fibrosis in a Murine Model of Unilateral Ureteral Obstruction

“…NOX4 is a main source of ROS in the kidney and plays an important role in renal fibrosis [ 64 ]. Previous studies have reported NOX4 upregulation in the UUO model [ 65 , 66 ]. Reduced expression of NOX4 contributed to the improvement of renal interstitial fibrosis in the UUO model [ 67 , 68 ].…”

Prediction of Regulatory SNPs in Putative Minor Genes of the Neuro-Cardiovascular Variant in Fabry Reveals Insights into Autophagy/Apoptosis and Fibrosis

“…The relationship between the process of apoptosis and the development of fibrosis has been seen in different models, Chung et al, 2021 [ 49 ] developed a mouse model with FD, analyzing the reaction of the kidneys to profibrotic or inflammatory stimuli secondary to ureteral obstruction, found that autophagy is altered in FD, leading to renal apoptosis and fibrosis formation. There are multiple studies on the relationship between these two processes, some that support that autophagy can promote cell death and others that, on the contrary, prevent death as the destination of the cell, some authors believe that perhaps the relationship is more than the autophagy only modifies the time of cell death [ 50 ].…”

miR−122−5p Regulates Renal Fibrosis In Vivo

“…LC3 is a key regulator of autophagy [ 45 ]. Previously, autophagy was reported to be induced in fibrotic kidneys and to have a protective effect against renal fibrosis [ 46 , 47 ]. Moreover, autophagy-deficiency (LC3-deficiency) promoted renal fibrosis [ 45 ].…”