Proteomic Analysis of Urinary Extracellular Vesicles from Patients with ADTKD-HNF1β identifies roles for cilia-related proteins and Serpins

ABSTRACT: Autosomal dominant tubulointerstitial kidney disease-subtype hepatocyte nuclear factor 1β (ADTKD-HNF1β) is caused by pathogenic variants in or deletions of the gene encoding transcription factor HNF1β. Patients with the same mutation have variable renal and extrarenal phenotypes, including renal cysts, diabetes, and electrolyte disturbances. The aim of this exploratory study was to provide insight whether pathophysiological effects in the kidney of ADTKD-HNF1β patients are visible by analysing their urinary extracellular vesicle (uEV) proteome. We isolated uEVs collected from patients with ADTKD-HNF1β and included patients with ADPKD and patients with CKD as controls. Subsequently, LC-MS/MS proteomics, and differential and pathway enrichment analyses were performed. Transcriptional targets of HNF1β were selected with ChIP-sequencing to study changes in protein abundance due to loss of HNF1β, and correlation analyses with clinical features were performed. We found differential enrichment of ciliary proteins IFT57, IFT74, IFT81 and IFT88 (adjusted p-value < 0.1), significant enrichment of pathways involved in cell-cell adhesion, and the depletion of several Serpins in patients with ADTKD-HNF1β and APDKD, compared to patients with CKD. We identified differential enrichment of nine HNF1β transcriptional targets between patients with ADTKD-HNF1β and patients with CKD, and we demonstrated that Serpin abundance negatively correlated with eGFR in patients with ADTKD-HNF1β (R = -0.52). The uEV proteome of patients with ADTKD-HNF1β shows a significant enrichment in proteins involved in renal cysts development, with resemblance to ADPKD. These changes provide new insight in the pathophysiology of ADTKD-HNF1β. Their onset and association with cyst development and kidney function decline warrants further study.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Urine, Extracellular Vesicle

DISEASE(S): Chronic Kidney Disease,Autosomal Dominant Disease,Polycystic Kidney Disease

SUBMITTER: Pascal Jansen  

LAB HEAD: Jeroen de Baaij

PROVIDER: PXD050720 | Pride | 2025-03-06

REPOSITORIES: Pride