Thyroid dysfunction in megalin deficient mice

Lisi, Simonetta; Segnani, Cristina; Mattii, Letizia; Botta, Roberta; Marcocci, Claudio; Dolfi, Amelio; McCluskey, Robert T.; Pinchera, Aldo; Bernardini, Nunzia; Marinò, Michele

doi:10.1016/j.mce.2005.03.009

Cited by 23 publications

(21 citation statements)

References 12 publications

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“…A similar situation, namely the presence of Tg and RAP in the absence of megalin, occurs in vivo in megalin deficient mice. In this regard, we have found that Tg secretion is normal in homozygous megalin deficient mice [13], which parallels the results presented here in COS-7 cells.…”

Section: Discussionsupporting

confidence: 90%

“…Overall, megalin-mediated transcytosis of Tg renders hormone release more effective, as it prevents lysosomal engulfment and wasteful transcytosis of hormone-rich Tg molecules [10]. Thus, megalin deficient mice are hypothyroid [13]. Whether this occurs also in humans is unknown, as thyroid function in Donnai-Barrow syndrome, the human counterpart of megalin deficiency [14], to our knowledge has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

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Intracellular retention of thyroglobulin in the absence of the low-density lipoprotein receptor-associated protein (RAP) is likely due to premature binding to megalin in the biosynthetic pathway

Lisi

Botta

Dottore

et al. 2016

J Endocrinol Invest

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Intracellular retention of thyroglobulin in the absence of the low-density lipoprotein receptor-associated protein (RAP) is likely due to premature binding to megalin in the biosynthetic pathway

Lisi

Botta

Dottore

et al. 2016

J Endocrinol Invest

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“…Megalin is also expressed extrarenally and is important for the transcytosis of thyroglobulin, the thyroid hormone precursor; thus, megalin-deficient mice suffer from hypothyroidism. 52 Although thyroid hormone levels have not been evaluated clinically or in monkeys, no obvious signs of hypothyroidism (e.g., goiter or weight gain) have been observed. As discussed earlier, an apparent controlled weight loss is often observed in humans 33 and monkeys administered bardoxolone methyl (probably because of the pharmacological effects of bardoxolone methyl on lipid handling and energy homeostasis).…”

Section: Discussionmentioning

confidence: 99%

Bardoxolone Methyl Decreases Megalin and Activates Nrf2 in the Kidney

Reisman

Chertow

Hebbar

et al. 2012

Journal of the American Society of Nephrology

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Inflammation and oxidative stress are hallmarks and mediators of the progression of CKD. Bardoxolone methyl, a potent activator of the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant and anti-inflammatory response, increases estimated GFR and decreases BUN, serum phosphorus, and uric acid concentrations in patients with moderate to severe CKD. However, it also increases albuminuria, which is associated with inflammation and disease progression. Therefore, we investigated whether this bardoxolone methyl-induced albuminuria may result from the downregulation of megalin, a protein involved in the tubular reabsorption of albumin and lipid-bound proteins. Administration of bardoxolone methyl to cynomolgus monkeys significantly decreased the protein expression of renal tubular megalin, which inversely correlated with the urine albuminto-creatinine ratio. Moreover, daily oral administration of bardoxolone methyl to monkeys for 1 year did not lead to any adverse effects on renal histopathologic findings but did reduce serum creatinine and BUN, as observed in patients with CKD. Finally, the bardoxolone methyl-induced decrease in megalin corresponded with pharmacologic induction of renal Nrf2 targets, including NAD(P)H:quinone oxidoreductase 1 enzyme activity and glutathione content. This result indicates that Nrf2 may have a role in megalin regulation. In conclusion, these data suggest that the increase in albuminuria that accompanies bardoxolone methyl administration may result, at least in part, from reduced expression of megalin, which seems to occur without adverse effects and with strong induction of Nrf2 targets. 23: 166323: -167323: , 201223: . doi: 10.1681 Pathogenic stimuli in patients with CKD and type 2 diabetes, including hypertension, obesity, heightened renin-angiotensin activity, and albuminuria, activate oxidative stress-mediated inflammation. [1][2][3][4][5] Indeed, oxidative stress and impaired antioxidant capacity intensify with progression of CKD, 6,7 and production of reactive oxygen species and oxidative stress result in activation of the transcription factor nuclear factor kB (NFkB). NFkB regulates expression of proinflammatory cytokines and chemokines, and its pathologic activation is a hallmark of many inflammatory disorders, including CKD. Activated NFkB is present in the kidneys of patients with diabetic nephropathy but is undetectable in normal healthy kidneys. 8 Thus, oxidative stress facilitates proinflammatory signaling, which frequently results in further oxidative stress, thereby creating a destructive feedback loop and, often, perturbation of normal physiologic processes and disease progression. J Am Soc NephrolTo respond to oxidative and electrophilic stimuli, organisms have developed elaborate cytoprotective pathways that are directly regulated by the

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“…As RBP is also a megalin ligand, it was proposed that this renal receptor had a role in TTR-mediated renal reuptake of T 4 . In fact, megalin KO mice were shown to be hypothyroid as supported by the significantly reduced T 4 serum levels (34). Nevertheless, the hypothyroid phenotype was related with the fact that megalin mediates transcytosis of thyroglobulin (Tg), the thyroid hormone precursor, resulting in its reuptake.…”

Section: Megalin: the Receptor For Renal Uptake Of Ttrmentioning

confidence: 99%

Aboard transthyretin: From transport to cleavage

et al. 2010

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SummaryTransthyretin (TTR) is a plasma and cerebrospinal fluid protein mainly recognized as the transporter of thyroxine (T 4 ) and retinol. Mutated TTR leads to familial amyloid polyneuropathy, a neurodegenerative disorder characterized by TTR amyloid deposition particularly in peripheral nerves. Beside its transport activities, TTR is a cryptic protease and participates in the biology of the nervous system. Several studies have been directed at finding new ligands of TTR to further explore the biology of the protein. From the identified ligands, some were in fact TTR protease substrates. In this review, we will discuss the existent information concerning TTR ligands/substrates. 2010 IUBMB IUBMB Life, 62(6): [429][430][431][432][433][434][435] 2010

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Thyroid dysfunction in megalin deficient mice

Cited by 23 publications

References 12 publications

Intracellular retention of thyroglobulin in the absence of the low-density lipoprotein receptor-associated protein (RAP) is likely due to premature binding to megalin in the biosynthetic pathway

Intracellular retention of thyroglobulin in the absence of the low-density lipoprotein receptor-associated protein (RAP) is likely due to premature binding to megalin in the biosynthetic pathway

Bardoxolone Methyl Decreases Megalin and Activates Nrf2 in the Kidney

Aboard transthyretin: From transport to cleavage

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