Urinary Exosomes of Patients with Cystic Fibrosis Unravel CFTR-Related Renal Disease.

Sebastien Gauthier,Alexandre Hinzpeter,Michaela Semeraro,Iwona Pranke,Vincent Jung,Véronique Stoven,Isabelle Sermet-Gaudelus,Loredana Martignetti,Aleksander Edelman,Thao Nguyen-Khoa,Ida Chiara Guerrera

doi:10.3390/ijms21186625

Abstract

Background: The prevalence of chronic kidney disease is increased in patients with cystic fibrosis (CF). The study of urinary exosomal proteins might provide insight into the pathophysiology of CF kidney disease. Methods: Urine samples were collected from 19 CF patients (among those 7 were treated by cystic fibrosis transmembrane conductance regulator (CFTR) modulators), and 8 healthy subjects. Urine exosomal protein content was determined by high resolution mass spectrometry. Results: A heatmap of the differentially expressed proteins in urinary exosomes showed a clear separation between control and CF patients. Seventeen proteins were upregulated in CF patients (including epidermal growth factor receptor (EGFR); proteasome subunit beta type-6, transglutaminases, caspase 14) and 118 were downregulated (including glutathione S-transferases, superoxide dismutase, klotho, endosomal sorting complex required for transport, and matrisome proteins). Gene set enrichment analysis revealed 20 gene sets upregulated and 74 downregulated. Treatment with CFTR modulators yielded no significant modification of the proteomic content. These results highlight that CF kidney cells adapt to the CFTR defect by upregulating proteasome activity and that autophagy and endosomal targeting are impaired. Increased expression of EGFR and decreased expression of klotho and matrisome might play a central role in this CF kidney signature by inducing oxidation, inflammation, accelerated senescence, and abnormal tissue repair. Conclusions: Our study unravels novel insights into consequences of CFTR dysfunction in the urinary tract, some of which may have clinical and therapeutic implications.

Highlights

Cystic fibrosis (CF) is a life limiting disease due to mutations in the cystic fibrosis conductance gene regulator (CFTR)
Kidney has not attracted the most attention in CF, our data indicate that this organ might suffer from tissue injury, and suggests a risk to evolve to chronic kidney disease upon patients’ ageing
This is the first study showing that CF pathobiology modifies urinary exosome protein composition, and generates potential CF exosomal biomarkers

Summary

Introduction

Cystic fibrosis (CF) is a life limiting disease due to mutations in the cystic fibrosis conductance gene regulator (CFTR). A spectrum of renal dysfunctions is described from birth in CF patients, including kidney stones, nephrocalcinosis, low molecular protein urinary loss, and increased renal clearance of drugs [3,4,5]. These abnormalities are encountered only in few patients and this contrasts with the high level of CFTR expression in the kidney [6]. Treatment with CFTR modulators yielded no significant modification of the proteomic content These results highlight that CF kidney cells adapt to the CFTR defect by upregulating proteasome activity and that autophagy and endosomal targeting are impaired. Conclusions: Our study unravels novel insights into consequences of CFTR dysfunction in the urinary tract, some of which may have clinical and therapeutic implications

Methods

Results

Conclusion