Single-nucleus Transcriptomics Reveals Precystic Dysfunction in Polycystic Kidney Disease

Abstract

Polycystic kidney disease (PKD) is the most common cause of end stage renal disease with a known genetic etiology. This disease is characterized by the progressive development and expansion of kidney cysts. While recent studies have shed light on cell types and states contributing to PKD progression following cyst formation, the biological processes at work prior to cyst formation are relatively unexplored. To better understand mechanisms contributing to cystogenesis, we analyze pre-cystic kidneys from Pkd1R3277C/R3277Cmice across multiple early timepoints, generating a transcriptomic atlas of nearly 1 million single nucleus transcriptomes. Activation of a small subset of genes in a precystic signaling pathway drives changes in both the distal convoluted tubule and proximal tubule cells. This pathway overlaps with a recently described "failed repair" transcriptomic signature despite the lack of clear changes in tissue morphology at these early stages of nascent cystogenesis. We identify Creb5 as a critical driver for cystogenesis. This single cell transcriptomic analysis of nascent cystogenesis reveals previously unrecognized cellular signaling at the earliest assessed points in precystic kidneys and provides a foundation for the development of high definition early diagnostic and therapeutic approaches prior to observable cysts in PKD.