Aquaporin‐3 deficiency slows cyst enlargement in experimental mouse models of autosomal dominant polycystic kidney disease

Abstract

Human autosomal dominant polycystic kidney disease (ADPKD) is characterized by bilateral renal cysts that lead to a decline in kidney function. Previous studies reported aquaporin (AQP)‐3 expression in cysts derived from collecting ducts in ADPKD. To study the role of AQP3 in cyst development, we generated 2 polycystic kidney disease (PKD) mouse models: kidney‐specific Pkd1 knockout mice and inducible Pkd1 knockout mice, each without and with AQP3 deletion. In both models, kidney sizes and cyst indexes were significantly reduced in AQP3‐null PKD mice compared with AQP3‐expressing PKD mice, with the difference seen mainly in collecting duct cysts. AQP3‐deficient kidneys showed significantly reduced ATP content, increased phosphorylated (p)‐AMPK, and decreased p‐ERK and p‐mammalian target of rapamycin (mTOR). In a matrix‐grown Madin‐Darby canine kidney cyst model, AQP3 expression promoted cyst enlargement and was associated with increased expression of hypoxia‐inducible factor 1‐α and glucose transporter 1 and increased glucose uptake. Our data suggest that the slowed renal cyst enlargement in AQP3 deficiency involves impaired energy metabolism in the kidney through AMPK and mTOR signaling and impaired cellular glucose uptake. These findings implicate AQP3 as a novel determinant of renal cyst enlargement and hence a potential drug target in ADPKD.—Wang, W., Geng, X., Lei, L., Jia, Y., Li, Y., Zhou, H., Verkman, A. S., Yang, B. Aquaporin‐3 deficiency slows cyst enlargement in experimental mouse models of autosomal dominant polycystic kidney disease. FASEB J. 33, 6185–6196 (2019). http://www.fasebj.org

<p>Hypoxia-Induced Aquaporin-3 Changes Hepatocellular Carcinoma Cell Sensitivity to Sorafenib by Activating the PI3K/Akt Signaling Pathway</p>

“…23 Wang and colleagues also found that AQP3 protein levels correlated with HIF-1α in a matrixgrown Madin-Darby canine kidney cyst model. 60 Therefore, we investigated whether changes in AQP3 expression affected hypoxic HCC cell sensitivity to sorafenib. We found that hypoxic cells transfected with lentivirus expressing AQP3 were less sensitive to sorafenib-induced apoptosis.…”

“…[20][21][22][23] AQP3's role in tumor progression, prognosis, and treatment has recently garnered attention. In addition to promoting tumor progression and metastasis, [24][25][26][27][28] AQP3 is involved in drug resistance in various malignant tumors. 29,30 AQP3 knockdown or knockout studies have demonstrated its role in various tumor types.…”

Aquaporins in the kidney: physiology and pathophysiology

“…AQP3-deficient kidneys of pkd1-null mice exhibit significantly reduced ATP content, increased phosphorylated (p-)AMP-activated protein kinase (AMPK), and decreased p-ERK and p-mTOR in parallel with reduced kidney size and cyst indexes. These findings imply that AQP3 may also participate in renal cyst enlargement and, thus, may be a potential drug target for ADPKD (93). In addition, recent studies have revealed that a single nucleotide mutation of the AQP11 gene and AQP11 gene knockout have disruptive PC-1 trafficking to the plasma membrane and consequently develop polycystic kidneys (74,84).…”

Ganoderic acid A is the effective ingredient of Ganoderma triterpenes in retarding renal cyst development in polycystic kidney disease

“…Approximately 400 MDCK cells were suspended in 0.4 mL of ice-cold MEM (Sigma-Aldrich, St. Louis, MO, USA) containing 2.9 mg/mL collagen (PureCol; Inamed Biomaterials, Fremont, CA, USA), 10 mM HEPES, 100 U/mL penicillin, and 100 μg/mL streptomycin (pH 7.4) in each well of a 24-well plate (Corning, NY, USA). Dulbecco’s modified Eagleʼs medium-F12 medium (DMEM-F12) containing 10% FBS and 10 μM FSK without or with GA monomers was added to each well and exchanged every 12 h. The relevant procedures were performed as previously described [ 20 ]. Micrographs of the cysts (≥30/group) were obtained with an inverted microscope (Nikon TE2000-S; Nikon Instruments, Melville, NY) on days 4, 6, 8, 10, and 12.…”