Abstract

Polycystic kidney disease (PKD) is an incurable degenerative disease affecting 12.5 million people worldwide. Numerous cysts form in the renal tubules, which progressively enlarge and damage the surrounding kidney tissues, severely reducing quality of life and leading most patients to kidney failure with the need for dialysis or transplant. Partly due to lack of knowledge of the precise PKD pathological mechanisms, therapeutic options are limited. The complex anatomy of the human and vertebrate kidney makes it difficult to define the PKD mechanisms and perform drug discovery. In contrast, the fruit fly Drosophila melanogaster shares high genetic conservation with humans and features anatomically isolated Malpighian (renal) tubules with physiologically diversified regions, making it an ideal model for studying renal cystogenesis and performing rapid drug discovery in vivo. One mimic of the second
mitochondria-derived activator of caspases (Smac), a class of pro-apoptotic molecules being developed for cancer therapy, was found to reduce renal cysts in a murine ADPKD model. Here, we used our first-in-kind Drosophila PKD model, the Bicaudal C mutant, to test the cyst-reducing properties of four novel Smac mimics. Smac mimicry was found to decrease the overall incidence of tubular cysts. Intriguingly, cysts were reduced at different rates along the Malpighian tubules, underscoring functional differences in the tubular regions. Thus, this study suggests novel hypotheses on the conservation of renal cystic mechanisms and the function of RNA-binding protein Bicaudal C in the renal tubule.