ADAR regulates APOL1 via A-to-I RNA editing by inhibition of MDA5 activation in a paradoxical biological circuit

APOL1-associated kidney disease occurs in some but not all individuals carrying two copies of APOL1 genetic risk variants. The factors leading to kidney disease are incompletely understood. Viral illnesses or other environmental triggers are likely needed to activate the production of APOL1 at toxic levels to cause kidney damage. We found that a type of RNA modification called adenosine-to-inosine (A-to-I) editing, carried out by ADAR, suppressed APOL1 gene expression mediated by inflammatory pathways. Moreover, APOL1's messenger RNA itself was notable for triggering inflammation if not modified by ADAR editing. A transgenic mouse model replicated the editing pattern of APOL1 messenger RNA. The findings indicate that ADAR functions as a break to counter APOL1's rapid production during acute inflammation.