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“Glomerular parietal epithelial cells (PECs) are precursors to podocytes in mature glomeruli; however, as progenitors, the distinct intrinsic mechanisms that allow for repeated periods of cell-cycle arrest and re-entry of PECs after glomerulogenesis are unknown. Here, we show that the Src-suppressed protein kinase C substrate (SSeCKS), a multivalent scaffolding A kinase anchoring protein, sequesters cyclin D1 in the cytoplasm of quiescent PECs. SSeCKS expression is induced in embryonic PECs, but not in embryonic podocytes, starting at the

S phase of glomerulogenesis, and is constitutively expressed postnatally by PECs, but not podocytes, in normal glomeruli. Cyclin D-1 was immunoprecipitated with SSeCKS from capsulated glomeruli containing PECs, whereas decapsulated glomeruli without PECs lacked SSeCKS and cyclin D1. BAY 11-7082 cost Cell-cell contact inhibition of proliferation in cultured PECs induced SSeCKS expression and binding of cyclin D1 by SSeCKS in the cytoplasm, whereas phosphorylation of SSeCKS by activated protein kinase C disrupted binding, resulting in nuclear translocation of cyclin D1. SSeCKS-/-

mice showed hyperplasia of PECs in otherwise normal glomeruli and developed significantly worse proteinuric glomerular disease, marked by increased PEC proliferation and expression of nuclear cyclin D-1, from nephrotoxic nephritis. These results suggest that SSeCKS controls the localization and activity of cyclin D1 in PECs and influences proliferative injury in the glomerulus. Laboratory Selleckchem Verubecestat Investigation (2012) 92, 499-510; doi:10.1038/labinvest.2011.199; published online 16 January 2012″
“Cocaine exposure produces sensitization that is partly mediated by cyclic adenosine monophosphate (cAMP) pathways within the nucleus accumbens (NAc). Type IV phosphodiesterases (PDE4s) break down cAMP and are required for cocaine-induced conditioned

place preference. Whether PDE4 disruption attenuates induction of behavioral sensitization to cocaine and subsequent NAc expression of phosphorylated extracellular signal-regulated kinase (ERK), which is involved in cocaine-induced sensitization, is unknown.

The objective of this study was this website to determine whether inhibition of PDE4s prevents cocaine-induced locomotor sensitization and if reduced behavioral sensitization is accompanied by decreased expression of phosphorylated ERK (pERK) within the NAc.

Mice were administered the PDE4 inhibitor, rolipram, or vehicle before or after five daily injections of cocaine or saline, and activity was monitored on days 1 and 5. After nine drug-free days, locomotor sensitization was tested. Some subjects were sacrificed following testing for behavioral sensitization to measure pERK expression in the NAc.

PDE4 inhibition, during the induction of sensitization, reduced behavioral sensitization only if rolipram (1.0 mg/kg) was administered before cocaine.