Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is caused by germline mutations of PKD1 or PKD2 on one allele and a somatic mutation inactivating the remaining normal allele. However, if and how null ADPKD gene renal epithelial cells affect the biology and function of neighboring cells, including heterozygous renal epithelial cells, fibroblasts and macrophages during cyst initiation and expansion remains unknown. Here we address this question with a “cystic extracellular vesicles/exosomes theory”. We show that cystic cell derived extracellular vesicles and urinary exosomes derived from ADPKD patients promote cyst growth in Pkd1 mutant kidneys and in 3D cultures. This is achieved by: 1) downregulation of Pkd1 gene expression and upregulation of specific miRNAs, resulting in the activation of PKD associated signaling pathways in recipient renal epithelial cells and tissues; 2) the activation of fibroblasts; and 3) the induction of cytokine expression and the recruitment of macrophages to increase renal inflammation in cystic kidneys. Inhibition of exosome biogenesis/release with GW4869 significantly delays cyst growth in aggressive and milder ADPKD mouse models, suggesting that targeting exosome secretion has therapeutic potential for ADPKD.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) is caused by germline mutations of PKD1 or PKD2 on one allele and a somatic mutation inactivating the remaining normal allele
We found that treatment with Pkd1-null cell extracellular vesicles (EVs)/exosomes decreased Pkd[1] messenger RNAs (mRNAs) in a dosedependent manner as examined by quantitative real-time reversetranscription polymerase chain reaction (Fig. 2a), resulting in the decrease of its gene product, polycystin 1 (PC1) in mouse inner medullary-collecting duct 3 (mIMCD3) cells (Fig. 2b)
We found that administration of Pkd1-null cell EVs/exosomes promoted cyst growth in kidneys from Pkd1RC/RC characterized by enlarged kidney size (Fig. 4a–c) and increased cystic index (Fig. 4d) and kidney weight/body weight (KW/BW) ratios (Fig. 4e) compared to those in kidneys from Pkd1RC/RC mice treated with PBS, PH2 cellderived EVs/exosomes (Supplementary Fig. 5a-e) and mIMCD3 cell-derived EVs/exosomes (Supplementary Fig. 6a-g), respectively
Summary
Autosomal dominant polycystic kidney disease (ADPKD) is caused by germline mutations of PKD1 or PKD2 on one allele and a somatic mutation inactivating the remaining normal allele. If and how null ADPKD gene renal epithelial cells affect the biology and function of neighboring cells, including heterozygous renal epithelial cells, fibroblasts and macrophages during cyst initiation and expansion remains unknown. We address this question with a “cystic extracellular vesicles/exosomes theory”. We provide evidence that cystic epithelial cellsecreted extracellular vesicles/exosomes regulate the biology and function of adjacent cells, including renal epithelial cells, fibroblasts, and macrophages, and contribute to renal cyst formation; inhibition of exosome biogenesis/release delays cyst growth in Pkd[1] mutant mouse kidneys. Our results support a “cystic extracellular vesicles/exosomes theory” in ADPKD, which leads to a better understanding of the roles of extracellular vesicles/exosomes in renal cyst formation, and provides a potential therapeutic strategy for ADPKD
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
