PKD1-FBW7 Axis in Proximal Tubules Drives Kidney Function in ADPKD

Background: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by cyst formation and a gradual decline in renal function. The prevailing dogma is that changes in kidney architecture, driven by cysts that could originate from different kidney segments, collectively contribute to renal function decline. However, precise mechanisms and specific roles of different kidney segments in linking cystic expansion to renal function decline remain largely unknown. Methods: To investigate this, we induced a form of proteome reprogramming by deleting Fbxw7, which encodes FBW7, the substrate recognition component of the SCFFBW7 E3 ubiquitin ligase, in different kidney segments using ADPKD mouse models. Results: We show that deleting Fbxw7 predominantly in proximal tubules, as opposed to collecting ducts, improves renal function without significantly altering the kidney weight-to-body weight ratio or gross cystic index observed in ADPKD. While there were no notable changes in fibrosis, proliferation, inflammation, or apoptosis, selective improvements were observed in ciliary defects along with a modest reduction of micro-cyst in the proximal tubules. These findings were attributed to the upregulation of FBW7 expression in the ADPKD setting. Conclusion: Our study underscores the importance of proximal tubules in maintaining renal function, albeit displaying a higher threshold for cyst formation compared to collecting ducts in ADPKD. Our study suggests that the FBW7-regulated protein network in proximal tubules is crucial for sensing architectural changes induced by cystic expansion and subsequently triggers renal function decline in ADPKD. Funding: NIDDK Support