Megalin/LRP2 Expression Is Induced by Peroxisome Proliferator-Activated Receptor -Alpha and -Gamma: Implications for PPARs' Roles in Renal Function

Cabezas, Felipe; Lagos, Jonathan; Céspedes, Carlos L.; Vio, Carlos P.; Bronfman, Miguel; Marzolo, María‐Paz

doi:10.1371/journal.pone.0016794

Cited by 54 publications

(49 citation statements)

References 98 publications

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“…The reabsorption of albumin in proximal tubular epithelial cells is accomplished through the effects of two receptor proteins, megalin and cubilin (Verroust et al 2002). The altered expression of these proteins can affect the reabsorption of albumin (Hosojima et al 2009, Cabezas et al 2011. In the present study, the proximal tubular expression of megalin and cubilin were markedly downregulated in GK rats with diabetic nephropathy, however, the expression was normalized after treatment with gliquidone.…”

Section: Discussioncontrasting

confidence: 38%

Gliquidone decreases urinary protein by promoting tubular reabsorption in diabetic Goto-Kakizaki rats

Ke¹,

Li²,

Xu³

et al. 2013

Journal of Endocrinology

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The efficacy of gliquidone for the treatment of diabetic nephropathy was investigated by implanting micro-osmotic pumps containing gliquidone into the abdominal cavities of Goto-Kakizaki (GK) rats with diabetic nephropathy. Blood glucose, 24 h urinary protein, and 24 h urinary albumin levels were measured weekly. After 4 weeks of gliquidone therapy, pathological changes in the glomerular basement membrane (GBM) were examined using an electron microscope. Real-time PCR, western blotting, and immunohistochemistry were employed to detect glomerular expression of receptors for advanced glycation end products (RAGE) (AGER), protein kinase C b (PKCb), and protein kinase A (PKA) as well as tubular expression of the albumin reabsorption-associated proteins: megalin and cubilin. Human proximal tubular epithelial cells (HK-2 cells) were used to analyze the effects of gliquidone and advanced glycation end products (AGEs) on the expression of megalin and cubilin and on the absorption of albumin. Gliquidone lowered blood glucose, 24 h urinary protein, and 24 h urinary albumin levels in GK rats with diabetic nephropathy. The level of plasma C-peptide increased markedly and GBM and podocyte lesions improved dramatically after gliquidone treatment. Glomerular expression of RAGE and PKCb decreased after gliquidone treatment, while PKA expression increased. AGEs markedly suppressed the expression of megalin and cubulin and the absorption of albumin in HK-2 cells in vitro, whereas the expression of megalin and cubilin and the absorption of albumin were all increased in these cells after gliquidone treatment. In conclusion, gliquidone treatment effectively reduced urinary protein in GK rats with diabetic nephropathy by improving glomerular lesions and promoting tubular reabsorption.

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Section: Discussioncontrasting

confidence: 38%

Gliquidone decreases urinary protein by promoting tubular reabsorption in diabetic Goto-Kakizaki rats

Ke¹,

Li²,

Xu³

et al. 2013

Journal of Endocrinology

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“…Renal handling of plasma proteins, of which albumin constitutes the majority, are reabsorbed by megalin/ cubilin-mediated endocytosis in tubular proximal epithelial cells (40). Caruso-Neves et al (41) showed that LLC-PK1 cells incubated with high concentrations of BSA exhibited a significant reduction in megalin mRNA and protein levels, but peroxisome proliferator-activated receptor ␣ and peroxisome proliferator-activated receptor ␥ agonists increased mRNA and/or protein levels of megalin (42). In contrast, a recent investigation indicated that megalin/cubilin receptor expression exhibited no significant difference in normal mice following a short-term albumin-overload or a model of focal segmental glomerulosis (FSGS) (43,44).…”

Section: Discussionmentioning

confidence: 99%

Megalin/Cubulin-Lysosome-mediated Albumin Reabsorption Is Involved in the Tubular Cell Activation of NLRP3 Inflammasome and Tubulointerstitial Inflammation

Liú

Wen

Tang

et al. 2015

Journal of Biological Chemistry

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Background: NLRP3 inflammasome activation is involved in albuminuria-induced renal injury. Results: The inhibition of megalin/cubilin or lysosomal cathepsin B reduced albuminuria-induced NLRP3 inflammasome activation. Conclusion: Megalin/cubilin and lysosome rupture is involved in albumin-triggered tubular injury and TI. Significance: This study provides novel insights into albuminuria-induced TI and implicates the active control of albuminuria as a critical strategy to halt the progression of CKD.

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“…Cubilin is co-expressed with megalin in numerous tissues [7,8,13,14], suggesting the possibility that the genes share common transcriptional regulatory mechanisms. Peroxisome proliferator-activated receptors (PPARs), transcription factors belonging to the nuclear receptor superfamily, upregulate megalin expression [15], but it is not yet known whether these factors influence cubilin expression. Furthermore, expression of megalin is regulated by histone acetylation and methylation and DNA methylation [16], but it is not yet known whether cubilin is regulated epigenetically in a similar manner.…”

Section: Introductionmentioning

confidence: 99%

Cubilin expression is monoallelic and epigenetically augmented via PPARs

et al. 2013

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BackgroundCubilin is an endocytic receptor that is necessary for renal and intestinal absorption of a range of ligands. Endocytosis mediated by cubilin and its co-receptor megalin is the principal mechanism for proximal tubule reabsorption of proteins from the glomerular filtrate. Cubilin is also required for intestinal endocytosis of intrinsic factor-vitamin B12 complex. Despite its importance, little is known about the regulation of cubilin expression.ResultsHere we show that cubilin expression is under epigenetic regulation by at least two processes. The first process involves inactivation of expression of one of the cubilin alleles. This monoallelic expression state could not be transformed to biallelic by inhibiting DNA methylation or histone deacetylation. The second process involves transcriptional regulation of cubilin by peroxisome proliferator-activated receptor (PPAR) transcription factors that are themselves regulated by DNA methylation and histone deacetylation. This is supported by findings that inhibitors of DNA methylation and histone deacetylation, 5Aza and TSA, increase cubilin mRNA and protein in renal and intestinal cell lines. Not only was the expression of PPARα and γ inducible by 5Aza and TSA, but the positive effects of TSA and 5Aza on cubilin expression were also dependent on both increased PPAR transcription and activation. Additionally, 5Aza and TSA had similar effects on the expression of the cubilin co-receptor, megalin.ConclusionsTogether, these findings reveal that cubilin and megalin mRNA expression is under epigenetic control and thus point to new avenues for overcoming pathological suppression of these genes through targeting of epigenetic regulatory processes.

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Megalin/LRP2 Expression Is Induced by Peroxisome Proliferator-Activated Receptor -Alpha and -Gamma: Implications for PPARs' Roles in Renal Function

Cited by 54 publications

References 98 publications

Gliquidone decreases urinary protein by promoting tubular reabsorption in diabetic Goto-Kakizaki rats

Gliquidone decreases urinary protein by promoting tubular reabsorption in diabetic Goto-Kakizaki rats

Megalin/Cubulin-Lysosome-mediated Albumin Reabsorption Is Involved in the Tubular Cell Activation of NLRP3 Inflammasome and Tubulointerstitial Inflammation

Cubilin expression is monoallelic and epigenetically augmented via PPARs

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