TNF-α induces Claudin-1 expression in renal tubules in Alport mice.

Claudin-1 (CL-1) is responsible for the paracellular barrier function of glomerular parietal epithelial cells (PEC) in kidneys, but the role of CL-1 in proximal tubules remains to be elucidated. In this study, to evaluate CL-1 as a potential therapeutic drug target for chronic kidney disease, we investigated change of CL-1 expression in the proximal tubules of diseased kidney and elucidated the factors that induced this change. We established Alport mice as a kidney disease model and investigated the expression of CL-1 in diseased kidney using quantitative PCR and immunohistochemistry (IHC).

Novel AXL-specific inhibitor ameliorates kidney dysfunction through the inhibition of epithelial-to-mesenchymal transition of renal tubular cells.

Chronic kidney diseases affect more than 800 million people globally and remain a high unmet need. Various therapeutic targets are currently under evaluation in pre-clinical and clinical studies. Because the growth arrest specific gene 6 (Gas6)/AXL pathway has been implicated in the pathogenesis of kidney diseases, we generated a novel selective and potent AXL inhibitor, CH5451098, and we evaluated its efficacy and elucidated its mechanism in an NEP25 mouse model that follows the clinical course of glomerular nephritis.

TUSC4/NPRL2, a novel PDK1-interacting protein, inhibits PDK1 tyrosine phosphorylation and its downstream signaling.

3-Phosphoinositide-dependent protein kinase-1 (PDK1) is a key regulator of cell proliferation and survival signal transduction. PDK1 is known to be constitutively active and is further activated by Src-mediated phosphorylation at the tyrosine-9, -373, and -376 residues. To identify novel regulators of PDK1, we performed E.

Casein kinase 2-interacting protein-1, a novel Akt pleckstrin homology domain-interacting protein, down-regulates PI3K/Akt signaling and suppresses tumor growth in vivo.

The serine/threonine kinase Akt plays a central role in cell survival and proliferation. Its activation is linked to tumorigenesis in several human cancers. Although many Akt substrates have been elucidated, the Akt-binding proteins that regulate Akt function remain unclear.

Prediction of drug-induced intrahepatic cholestasis: in vitro screening and QSAR analysis of drugs inhibiting the human bile salt export pump.

Drug-induced intrahepatic cholestasis is one of the major causes of hepatotoxicity, which often occur during the drug discovery and development process. Human ATP-binding cassette transporter ABCB11 (sister of P-glycoprotein/bile salt export pump) mediates the elimination of cytotoxic bile salts from liver cells to bile, and, therefore, plays a critical role in the generation of bile flow. The authors have recently developed in vitro high-speed screening and quantitative structure-activity relationship analysis methods to investigate the interaction of ABCB11 with a variety of compounds.

High-speed screening and QSAR analysis of human ATP-binding cassette transporter ABCB11 (bile salt export pump) to predict drug-induced intrahepatic cholestasis.

Human ATP-binding cassette transporter ABCB11 (SPGP/BSEP) mediates the elimination of bile salts from liver cells and thereby plays a critical role in the generation of bile flow. In the present study, we have developed in vitro high-speed screening and quantitative structure-activity relationship (QSAR) analysis methods to investigate the interaction of ABCB11 with a variety of drugs. Plasma membrane vesicles prepared from insect cells overexpressing human ABCB11 were used to measure the ATP-dependent transport of [14C]taurocholate.