Fig. 10. Working model of the “cystic extracellular vesicles/exosomes theory” in ADPKD.

Renal cysts in ADPKD are proposed to be clonal in nature (derive from a single cell) and can arise from cells with inherited heterozygous germline mutations of PKD1 or PKD2 on one allele and a somatic mutation inactivating the remaining normal allele (two-hit model). After the second hit, the homozygous PKD1 mutant renal epithelial cell may be via its secreted extracellular vesicles/exosomes, which can be secreted from apical and basolateral sides of cyst-lining epithelial cells, to affect the biology and function of neighboring cells, including heterozygous renal epithelial cells, fibroblasts, and macrophages during cyst initiation and expansion. In particular, cystic cell-derived EVs/exosomes could (1) lower the levels of polycystin to a critical threshold to promote Pkd1 heterozygous renal epithelial cell proliferation and cyst growth (“threshold model”); (2) activate interstitial renal fibroblasts to promote renal fibrosis; and (3) induce the recruitment of macrophages to pericystic and interstitial regions in cystic kidneys. Inhibition of exosome biogenesis and release with GW4869 delays cyst growth in vivo. This “cystic extracellular vesicles/exosomes theory” addresses a long-time issue in PKD field of if and how ADPKD gene null renal epithelial cells affect the biology and function of neighboring cells, which integrates the “two-hit model” and “threshold model” together in renal cyst initiation and progression, and suggests a therapeutic potential for ADPKD treatment by targeting abnormal exosome secretion.