scholarly journals Pkd1 mutation has no apparent effects on peroxisome structure or lipid metabolism

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0000962021
Author(s):  
Takeshi Terabayashi ◽  
Luis F. Menezes ◽  
Fang Zhou ◽  
Hongyi Cai ◽  
Peter J. Walter ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Kidney Disease ◽  
Autosomal Dominant ◽  
Peroxisome Biogenesis ◽  
Polycystic Kidney ◽  
Imaging Studies ◽  
C Terminus ◽  
Autosomal Dominant Polycystic Kidney ◽  
Mutant Cells

Background: Multiple studies of tissue and cell samples from patients and pre-clinical models of autosomal dominant polycystic kidney disease report abnormal mitochondrial function and morphology and suggest metabolic reprogramming is an intrinsic feature of this disease. Peroxisomes interact with mitochondria physically and functionally, and congenital peroxisome biogenesis disorders can cause various phenotypes, including mitochondrial defects, metabolic abnormalities and renal cysts. We hypothesized that a peroxisomal defect might contribute to the metabolic and mitochondrial impairments observed in autosomal dominant polycystic kidney disease. Methods: Using control and Pkd1-/-kidney epithelial cells, we investigated peroxisome abundance, biogenesis and morphology by immunoblotting, immunofluorescent and live cell imaging of peroxisome-related proteins and assayed peroxisomal specific β-oxidation. We further analyzed fatty acid composition by mass spectrometry in kidneys of Pkd1fl/fl; Ksp-Cre mice. We also evaluated peroxisome lipid metabolism in published metabolomics datasets of Pkd1 mutant cells and kidneys. Lastly, we investigated if the C-terminus or full-length polycystin-1 co-localize with peroxisome markers by imaging studies. Results: Peroxisome abundance, morphology and peroxisome-related protein expression in Pkd1 -/- cells were normal, suggesting preserved peroxisome biogenesis. Peroxisomal β-oxidation was not impaired in Pkd1-/-cells, and there was no obvious accumulation of very long chain fatty acids in kidneys of mutant mice. Re-analysis of published datasets provide little evidence of peroxisomal abnormalities in independent sets of Pkd1 mutant cells and cystic kidneys, while providing further evidence of mitochondrial fatty acid oxidation defects. Imaging studies with either full length polycystin-1 or its C-terminus, a fragment previously shown to go to the mitochondria, showed minimal co-localization with peroxisome markers restricted to putative mitochondrion-peroxisome contact sites. Conclusions: Our studies showed that loss of Pkd1 does not disrupt peroxisome biogenesis nor peroxisome-dependent fatty acid (FA) metabolism.

scholarly journals Pkd1 mutation has no apparent effects on peroxisome structure or lipid metabolism

2021 ◽  
Author(s):  
Takeshi Terabayashi ◽  
Luis F Menezes ◽  
Fang Zhou ◽  
Hongyi Cai ◽  
Peter J Walter ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Autosomal Dominant ◽  
Acid Metabolism ◽  
Acid Oxidation ◽  
Peroxisome Biogenesis ◽  
Polycystic Kidney ◽  
Imaging Studies ◽  
C Terminus ◽  
Autosomal Dominant Polycystic Kidney ◽  
Mutant Cells

AbstractBackgroundMultiple studies of tissue and cell samples from patients and pre-clinical models of autosomal dominant polycystic kidney disease report abnormal mitochondrial function and morphology and suggest metabolic reprogramming is an intrinsic feature of this disease. Peroxisomes interact with mitochondria physically and functionally, and congenital peroxisome biogenesis disorders can cause various phenotypes, including mitochondrial defects, metabolic abnormalities and renal cysts. We hypothesized that a peroxisomal defect might contribute to the metabolic and mitochondrial impairments observed in autosomal dominant polycystic kidney disease.MethodsUsing control and Pkd1-/- kidney epithelial cells, we investigated peroxisome abundance, biogenesis and morphology by immunoblotting, immunofluorescent and live cell imaging of peroxisome-related proteins and assayed peroxisomal specific β-oxidation. We further analyzed fatty acid composition by mass spectrometry in kidneys of Pkd1fl/fl; Ksp-Cre mice. We also evaluated peroxisome lipid metabolism in published metabolomics datasets of Pkd1 mutant cells and kidneys. Lastly, we investigated if the C-terminus or full-length polycystin-1 co-localize with peroxisome markers by imaging studies.ResultsPeroxisome abundance, morphology and peroxisome-related protein expression in Pkd1-/- cells were normal, suggesting preserved peroxisome biogenesis. Peroxisomal β-oxidation was not impaired in Pkd1-/- cells, and there was no obvious accumulation of very long chain fatty acids in kidneys of mutant mice. Re-analysis of published datasets provide little evidence of peroxisomal abnormalities in independent sets of Pkd1 mutant cells and cystic kidneys, while providing further evidence of mitochondrial fatty acid oxidation defects. Imaging studies with either full length polycystin-1 or its C-terminus, a fragment previously shown to go to the mitochondria, showed minimal co-localization with peroxisome markers.ConclusionsOur studies showed that loss of Pkd1 does not disrupt peroxisome biogenesis nor peroxisome-dependent fatty acid metabolism.Key points-While mitochondrial abnormalities and fatty acid oxidation impairment have been reported in ADPKD, no studies have investigated if peroxisome dysfunction contributes to these defects.-We investigated peroxisome morphology, biogenesis and function in cell and animal models of ADPKD and investigated whether polycystin-1 co-localized with peroxisome proteins.-Our studies show that loss of Pkd1 does not disrupt peroxisome biogenesis nor peroxisome-dependent fatty acid metabolism.

scholarly journals Cellular Activation Triggered by the Autosomal Dominant Polycystic Kidney Disease Gene Product PKD2

1999 ◽  
Vol 19 (5) ◽  
pp. 3423-3434 ◽  
Author(s):  
Thierry Arnould ◽  
Lorenz Sellin ◽  
Thomas Benzing ◽  
Leonidas Tsiokas ◽  
Herbert T. Cohen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Germ Line ◽  
Signaling Cascades ◽  
Polycystic Kidney ◽  
Functional Connection ◽  
C Terminus ◽  
Mitogen Activated Protein ◽  
Autosomal Dominant Polycystic Kidney

ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is caused by germ line mutations in at least three ADPKD genes. Two recently isolated ADPKD genes, PKD1 and PKD2, encode integral membrane proteins of unknown function. We found that PKD2 upregulated AP-1-dependent transcription in human embryonic kidney 293T cells. The PKD2-mediated AP-1 activity was dependent upon activation of the mitogen-activated protein kinases p38 and JNK1 and protein kinase C (PKC) ɛ, a calcium-independent PKC isozyme. Staurosporine, but not the calcium chelator BAPTA [1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetate], inhibited PKD2-mediated signaling, consistent with the involvement of a calcium-independent PKC isozyme. Coexpression of PKD2 with the interacting C terminus of PKD1 dramatically augmented PKD2-mediated AP-1 activation. The synergistic signaling between PKD1 and PKD2 involved the activation of two distinct PKC isozymes, PKC α and PKC ɛ, respectively. Our findings are consistent with others that support a functional connection between PKD1 and PKD2 involving multiple signaling pathways that converge to induce AP-1 activity, a transcription factor that regulates different cellular programs such as proliferation, differentiation, and apoptosis. Activation of these signaling cascades may promote the full maturation of developing tubular epithelial cells, while inactivation of these signaling cascades may impair terminal differentiation and facilitate the development of renal tubular cysts.

scholarly journals Chlamydomonas PKD2 organizes mastigonemes, hair-like glycoprotein polymers on cilia

2020 ◽  
Vol 219 (6) ◽  
Author(s):  
Peiwei Liu ◽  
Xiaochu Lou ◽  
Jenna L. Wingfield ◽  
Jianfeng Lin ◽  
Daniela Nicastro ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Related Function ◽  
Ciliary Beating ◽  
Autosomal Dominant Polycystic Kidney ◽  
Extracellular Structures ◽  
Mutant Cells

Mutations in the channel protein PKD2 cause autosomal dominant polycystic kidney disease, but the function of PKD2 in cilia remains unclear. Here, we show that PKD2 targets and anchors mastigonemes, filamentous polymers of the glycoprotein MST1, to the extracellular surface of Chlamydomonas cilia. PKD2–mastigoneme complexes physically connect to the axonemal doublets 4 and 8, positioning them perpendicular to the plane of ciliary beating. pkd2 mutant cilia lack mastigonemes, and mutant cells swim with reduced velocity, indicating a motility-related function of the PKD2–mastigoneme complex. Association with both the axoneme and extracellular structures supports a mechanosensory role of Chlamydomonas PKD2. We propose that PKD2–mastigoneme arrays, on opposing sides of the cilium, could perceive forces during ciliary beating and transfer these signals to locally regulate the response of the axoneme.

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