Inhibition of NF-κB-dependent Bcl-xL expression by clusterin promotes albumin-induced tubular cell apoptosis

Takase, Osamu; Minto, Andrew W.; Puri, Tipu S.; Cunningham, Patrick N.; Jacob, Ammini K.; Hayashi, Matsuhiko; Quigg, Richard J.

doi:10.1038/sj.ki.5002563

Cited by 62 publications

(48 citation statements)

References 62 publications

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“…One of these 13 candidate genes, Bcl2l1, belongs to the Bcl-2 family, which is known to consist of anti-apoptotic genes expressed in renal tubular cells. [37][38][39][40] Transgenic mice deficient in Bcl-2 have renal hypoplasia and distal tubular damage, whereas other regions of the nephron such as glomeruli and proximal tubules seem unaffected in these mice. 41 Bcl2l1 is an interesting candidate gene in our model because the Rf-1 ϩ 3ϩ4_b line shows severe tubular dilation and protein casting at an early age.…”

Section: Discussionmentioning

confidence: 99%

Refined Mapping of the Renal Failure Rf-3 Quantitative Trait Locus

O’Meara

Lazar

Hoffman

et al. 2011

Journal of the American Society of Nephrology

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Rf-3, a quantitative trait locus (QTL) on rat chromosome 3, affects the development of CKD in FawnHooded Hypertensive (FHH) rats. This QTL spans 110 Mb and approximately 1400 genes; therefore, narrowing the position of this locus is necessary to elucidate potential candidate genes. Here, we used congenic models and comparative genomics to refine the Rf-3 candidate region. We generated congenic lines carrying smaller intervals (subcongenics) of the Rf-3 region and used these lines to reduce the Rf-3 candidate region by 94% (to 7.1 Mb). We used comparative genomics to identify QTL for both nephropathy and albuminuria in the syntenic region of this interval for both human and mouse. We also used the overlapping homologous regions to reduce the number of likely positional candidate genes to 13 known or predicted genes. By combining congenic models and cross-species studies, we narrowed the list of candidate genes to a level that we could sequence the whole interval to further identify the causative gene in future studies.

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Section: Discussionmentioning

confidence: 99%

Refined Mapping of the Renal Failure Rf-3 Quantitative Trait Locus

O’Meara

Lazar

Hoffman

et al. 2011

Journal of the American Society of Nephrology

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“…The migratory function of the HK-2 cells was measured using 24-well-modified Boyden chambers (Corning Life Sciences, Oneonta, NY, USA). Following transfection and treatment as described above, the cells (1x10 4 ) were detached, resuspended and seeded onto the filters (8-µm pore size) in the top compartment of the chamber. Following incubation at 37̊C for 24 h, the membrane was washed with PBS and fixed with 4% paraformaldehyde for 15 min at room temperature.…”

Section: Measurement Of Intracellular Rosmentioning

confidence: 99%

“…Renal tubulointerstitial inflammation plays a central role in the loss of renal function in CKD by promoting the expression of pro-inflammatory cytokines, the generation of reactive oxygen species (ROS) and cell apoptosis, ultimately leading to renal fibrosis (3,4). Consistently, the extent of inflammation positively correlates with kidney function and may be used to predict long-term prognosis in some clinical settings (5).…”

Section: Introductionmentioning

confidence: 99%

Oxidized high-density lipoprotein impairs the function of human renal proximal tubule epithelial cells through CD36

Gao

Qian

et al. 2014

International Journal of Molecular Medicine

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Abstract. Unlike native high-density lipoprotein (HDL), oxidized HDL exerts adverse effects in a number of diseases, including chronic kidney disease (CKD); however, the mechanisms involved in this process remain unclear. In the present study, we investigated the effects of oxidized HDL on renal tubular cells, which play an important role in the progression of CKD. Human renal proximal tubule epithelial cells (HK-2) were cultured and stimulated with various concentrations of oxidized HDL in the absence or presence of CD36 siRNA. The results revealed that oxidized HDL enhanced the production of reactive oxygen species (ROS) and upregulated the expression of pro-inflammatory factors in the HK-2 cells in a dose-dependent manner. Incubation with oxidized HDL also increased the apoptosis of the HK-2 cells and reduced their migration ability in a dose-dependent manner. Src family kinase, mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) were activated following stimulation with oxidized HDL. All these effects mediated by oxidized HDL on HK-2 cells were markedly attenuated by transfection with with CD36 siRNA pior to stimulation with oxidized HDL. These findings suggest that oxidized HDL enhances the pro-inflammatory properties and impairs the function of HK-2 cells, mainly through the scavenger receptor, CD36, as well as through the Src, MAPK and NF-κB pathways.

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“…[1][2][3][4] Tubular cell apoptosis has been demonstrated during albumin treatment of cultured renal tubular cells, in proteinuric animal models and also in human patients with nephrotic syndromes. [5][6][7][8][21][22][23] Although both extrinsic and intrinsic pathways of apoptosis have been shown to contribute to tubular apoptosis during proteinuria, 5-7 recent studies have further suggested the involvement of ER stress. 8 Despite these findings, very little is known about the upstream signaling that leads to the activation of the apoptotic pathways.…”

Section: Discussionmentioning

confidence: 99%

PKC-δ Promotes Renal Tubular Cell Apoptosis Associated with Proteinuria

Li¹,

Pabla²,

Wei³

et al. 2010

Journal of the American Society of Nephrology

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Proteinuria may contribute to progressive renal damage by inducing tubulointerstitial inflammation, fibrosis, and tubular cell injury and death, but the mechanisms underlying these pathologic changes remain largely unknown. Here, in a rat kidney proximal tubular cell line (RPTC), albumin induced apoptosis in a time-and dose-dependent manner. Caspase activation accompanied albumin-induced apoptosis, and general caspase inhibitors could suppress this activation. In addition, Bcl-2 transfection inhibited apoptosis and attenuated albumin-induced Bax translocation to mitochondria and cytochrome c release from the organelles, further confirming a role for the intrinsic pathway of apoptosis in albuminuria-associated tubular apoptosis. We observed phosphorylation and activation of PKC-␦ early during treatment of RPTC cells with albumin. Rottlerin, a pharmacologic inhibitor of PKC-␦, suppressed albumin-induced Bax translocation, cytochrome c release, and apoptosis. Moreover, a dominant-negative mutant of PKC-␦ blocked albumin-induced apoptosis in RPTC cells. In vivo, we observed activated PKC-␦ in proteinuric kidneys of streptozotocin-induced diabetic mice and in kidneys after direct albumin overload. Notably, albumin overload induced apoptosis in renal tubules, which was less severe in PKC-␦-knockout mice. Taken together, these results suggest that activation of PKC-␦ promotes tubular cell injury and death during albuminuria, broadening our understanding of the pathogenesis of progressive proteinuric kidney diseases.

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Inhibition of NF-κB-dependent Bcl-xL expression by clusterin promotes albumin-induced tubular cell apoptosis

Cited by 62 publications

References 62 publications

Refined Mapping of the Renal Failure Rf-3 Quantitative Trait Locus

Refined Mapping of the Renal Failure Rf-3 Quantitative Trait Locus

Oxidized high-density lipoprotein impairs the function of human renal proximal tubule epithelial cells through CD36

PKC-δ Promotes Renal Tubular Cell Apoptosis Associated with Proteinuria

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