In renal cystic diseases, sustained enlargement of fluid-filled
cysts is associated with severe interstitial
fibrosis and progressive loss of functioning nephrons.
Periostin, a matricellular
protein, is highly overexpressed in
cyst-lining epithelial cells of autosomal-dominant polycystic disease kidneys (
ADPKD) compared with normal tubule cells.
Periostin accumulates in situ within the matrix subjacent to
ADPKD cysts, binds to αVβ3 and αVβ5
integrins, and stimulates the
integrin-linked kinase to promote cell proliferation. We knocked out
periostin (Postn) in pcy/pcy mice, an orthologous model of nephronophthisis type 3, to determine whether
periostin loss reduces PKD progression in a slowly progressive model of renal cystic disease. At 20 weeks of age, pcy/pcy:Postn(-/-) mice had a 34% reduction in kidney
weight/body weight, a reduction in
cyst number and total cystic area, a 69% reduction in phosphorylated S6, a downstream component of the mTOR pathway, and fewer proliferating cells in the kidneys compared with pcy/pcy:Postn(+/+) mice. The pcy/pcy
Postin knockout mice also had less interstitial
fibrosis with improved renal function at 20 weeks and significantly longer survival (51.4 compared with 38.0 weeks). Thus,
periostin adversely modifies the progression of renal cystic disease by promoting
cyst epithelial cell proliferation,
cyst enlargement, and interstitial
fibrosis, all contributing to the decline in renal function and premature death.