Osteopontin deletion attenuates cyst growth but exacerbates fibrosis in mice with cystic kidney disease.

Osteopontin (OPN) is a multi-functional glycoprotein that coordinates the innate immune response, prevents nanocrystal formation in renal tubule fluid, and is a biomarker for kidney injury. OPN expression is markedly increased in cystic epithelial cells of polycystic kidney disease (PKD) kidneys; however, its role in PKD progression remains unclear. We investigated the in vitro effects of recombinant OPN on the proliferation of tubular epithelial cells from PKD and normal human kidneys and in vivo effects of OPN deletion on kidney cyst formation, fibrosis, and mineral metabolism in pcy/pcy mice, a non-orthologous model of autosomal-dominant PKD. In vitro studies revealed that OPN enhanced the proliferation of PKD cells but had no effect on normal kidney cells. Deletion of OPN in pcy/pcy mice significantly reduced kidney cyst burden; however, this was accompanied by increased fibrosis and no change in kidney function. The loss of OPN had no effect on kidney macrophage numbers, cyst epithelial cell proliferation, or apoptosis. Furthermore, there was no difference in kidney mineral deposition or mineral metabolism parameters between pcy/pcy mice with and without OPN expression. Global deletion of OPN reduced kidney cyst burden, while paradoxically exacerbating kidney fibrosis in mice with cystic kidney disease.

Jansson KP ，Kuluva J ，Zhang S ，Swanson T ，Zhang Y ，Zimmerman KA ，Fields TA ，Wallace DP ，Rowe PS ，Stubbs JR ... -  《Physiological Reports》

Periostin promotes renal cyst growth and interstitial fibrosis in polycystic kidney disease.

Wallace DP ，White C ，Savinkova L ，Nivens E ，Reif GA ，Pinto CS ，Raman A ，Parnell SC ，Conway SJ ，Fields TA ... -  《-》

Periostin overexpression in collecting ducts accelerates renal cyst growth and fibrosis in polycystic kidney disease.

Raman A ，Parnell SC ，Zhang Y ，Reif GA ，Dai Y ，Khanna A ，Daniel E ，White C ，Vivian JL ，Wallace DP ... -  《-》

Deficiency of geranylgeranyl biphosphate synthase in kidney tubules causes cystic kidney disease.

Polycystic kidney disease (PKD) is a common hereditary kidney disease. Although PKD occurrence is associated with certain gene mutations, its onset regulatory mechanisms are still not well understood. Here, we first report that the key enzyme geranylgeranyl diphosphate synthase (GGPPS) is specifically expressed in renal tubular epithelial cells of mouse kidneys. We aimed to explore the role of GGPPS in PKD. In this study, we established a Ggppsfl/fl:Cdh16cre mouse model and compared its phenotype with that of wild-type mice. A Ggpps-downregulation HK2 cell model was also used to further determine the role of GGPPS. We found that GGPPS was specifically expressed in renal tubular epithelial cells of mouse kidneys. Its expression also increased with age. Low GGPPS expression was observed in human ADPKD tissues. In the Ggppsfl/fl:Cdh16cre mouse model, Ggpps deletion in renal tubular epithelial cells induced the occurrence and development of renal tubule cystic dilation and caused the death of mice after birth due to abnormal renal function. Enhanced proliferation of cyst-lining epithelial cells was also observed after the knockout of Ggpps. These processes were related to the increased rate of Rheb on membrane/cytoplasm and hyperactivation of mTORC1 signaling. In conclusion, the deficiency of GGPPS in kidney tubules induced the formation of renal cysts. It may play a critical role in PKD pathophysiology. A novel therapeutic strategy could be designed according to this work.

Shao X ，Wang K ，Wu J ，Ma X ，Zhao Y ，Xu T ，Dai C ，Zhang F ，Wang Y ，Ren X ，Lu K ，Yin Z ，Guo B ，Cao C ，Xu X ，Xue B ... -  《-》

Dietary phosphate restriction attenuates polycystic kidney disease in mice.

Omede F ，Zhang S ，Johnson C ，Daniel E ，Zhang Y ，Fields TA ，Boulanger J ，Liu S ，Ahmed I ，Umar S ，Wallace DP ，Stubbs JR ... -  《-》