Extracellular vesicles and exosomes generated from cystic renal epithelial cells promote cyst growth in autosomal dominant polycystic kidney disease

• Published in: Nature communications Vol. 12; no. 1; p. 4548
• Main Authors: Ding, Hao, Li, Linda Xiaoyan, Harris, Peter C., Yang, Junwei, Li, Xiaogang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27-07-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/51; 14/28; 14/63; 38/109; 38/22; 38/77; 59; 59/5; 59/57; 631/80; 631/80/313/1481; 692/4022; 692/699/1585/1589; ADPKD gene; Alleles; Aniline Compounds - pharmacology; Animal models; Animals; Benzylidene Compounds - pharmacology; Biology; Cell Line; Cell Proliferation - drug effects; Collagen; Cysts; Cysts - pathology; Cytokines; Epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelium; Evolution; Exosomes; Exosomes - drug effects; Exosomes - metabolism; Extracellular vesicles; Fibroblasts; Fibrosis; Gene expression; Gene Expression Regulation - drug effects; Humanities and Social Sciences; Kidney - pathology; Kidney diseases; Kidneys; Macrophages; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Models, Biological; multidisciplinary; Mutation; Mutation - genetics; Polycystic kidney; Polycystic kidney disease 1 protein; Polycystic Kidney, Autosomal Dominant - genetics; Polycystic Kidney, Autosomal Dominant - pathology; Polycystic Kidney, Autosomal Dominant - urine; Rats; Science; Science (multidisciplinary); Signal Transduction - drug effects; Tetraspanin 30 - metabolism; TRPP Cation Channels - metabolism; Vesicles
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-24799-x

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.
Autosomal dominant polycystic kidney disease is characterized by the formation of cysts in the kidney. Here the authors show that cystic extracellular vesicles/exosomes play a critical role in regulating the biology and function of adjacent cells, including renal epithelial cells, fibroblasts and macrophages, and contribute to renal cyst growth.