Role of FBW7 in cystic diseases of the kidney - Polycystic Kidney Disease is the common denominator in several phenotypically diverse genetic conditions of the kidney. These diseases include Autosomal Dominant Polycystic Kidney Disease (ADPKD), Autosomal Recessive Polycystic Kidney Disease, Nephronophthisis (NPHP), and Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD). NPHP, which can also be implicated in syndromic forms of PKD such as Joubert, Bardet-Biedl, and Meckel-Gruber syndrome, together with ADTKD account for 10-20% of children with chronic renal failure and for 1-5% of all patients undergoing dialysis or transplantation. Mechanisms of cyst development have been extensively studied using a wide variety of genetic, biochemical, functional, and pharmacological approaches. While significant progress has been made in identifying the involvement of signaling pathways and key organelles in disease pathophysiology, the step-by-step mechanisms mediating the architectural and structural changes of tubular cells during cyst formation and expansion are incompletely understood. It is becoming increasingly clear that both intrinsic processes such as cell signaling, cell death, and proliferation, as well as extrinsic factors, such as fibrosis and inflammation influence cystic growth and expansion. Understanding these processes would be of paramount importance in identifying new, more effective, and specific targets for pharmacologic intervention. We undertook an approach of proteome reprogramming by deleting the Fbxw7 gene in tubular cells to identify protein networks responsible for cystogenesis. FBW7 (gene name, Fbxw7) is the recognition receptor of the SCFFBW7 E3 ligase which processes numerous proteins for ubiquitin-mediated degradation. Mutant mice developed slowly progressing cystic kidney disease without kidney enlargement, tubulointerstitial fibrosis, tubular degeneration, and an overall gradual decline in kidney function. These are cardinal features of NPHP and ADTKD. Aided by the ability to identify direct FBW7 targets, we have identified protein networks with potential roles in cystogenesis, fibrosis, and tubular degermation. Using this information, we now aim at understanding how cystogenesis develops, how it is modulated by fibrosis and/or tubular degeneration, and how these processes impact overall renal function. Successful completion of the proposed studies will enhance our understanding of cellular mechanisms of cystogenesis, fibrosis, and tubular degeneration and aid in the identification of new therapeutic targets for PKD.
