Induction of retinopathy by fibrillar oxalate assemblies.
Dor ZaguriShira Shaham-NivEfrat NaamanMichael MimouniDaniella MagenShirley PollackTopaz KreiserRina LeibuSigal Rencus-LazarLihi Adler-AbramovichIdo PerlmanEhud GazitShiri Zayit-SoudryPublished in: Communications chemistry (2020)
The formation of metabolite fibrillar assemblies represents a paradigm shift in the study of human metabolic disorders. Yet, direct clinical relevance has been attributed only to metabolite crystals. A notable example for metabolite crystallization is calcium oxalate crystals observed in various diseases, including primary hyperoxaluria. We unexpectedly observed retinal damage among young hyperoxaluria patients in the absence of crystals. Exploring the possible formation of alternative supramolecular organizations and their biological role, here we show that oxalate can form ordered fibrils with no associated calcium. These fibrils inflict intense retinal cytotoxicity in cultured cells. A rat model injected with oxalate fibrils recaptures patterns of retinal dysfunction observed in patients. Antibodies purified from hyperoxaluria patient sera recognize oxalate fibrils regardless of the presence of calcium. These findings highlight a new molecular basis for oxalate-associated disease, and to our knowledge provide the first direct clinical indication for the pathogenic role of metabolite fibrillar assemblies.
Keyphrases
- end stage renal disease
- newly diagnosed
- chronic kidney disease
- ejection fraction
- optical coherence tomography
- diabetic retinopathy
- endothelial cells
- oxidative stress
- prognostic factors
- peritoneal dialysis
- room temperature
- patient reported outcomes
- cell death
- induced pluripotent stem cells
- signaling pathway
- endoplasmic reticulum stress
- quantum dots
- pi k akt
- energy transfer