Endocytic receptor LRP2/megalin—of holoprosencephaly and renal Fanconi syndrome

Willnow, Thomas E.; Christ, Annabel

doi:10.1007/s00424-017-1992-0

Cited by 38 publications

(32 citation statements)

References 105 publications

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“…Megalin is expressed in many extrarenal cell types and is necessary for organ development and tissue functions related to protein uptake as it binds a number of specific ligands. There is some information about megalin, also known as LRP2 or gp330, and kidney health, such as in "megalinopathies," associated with null mutations (32) and with megalin dysfunction (33)(34)(35). It has also been suggested that megalin is involved in both development of and recovery from some types of acute kidney injury (36).…”

Section: Discussionmentioning

confidence: 99%

Megalin mediates 25‐hydroxyvitamin D₃actions in human mesenchymal stem cells

et al. 2019

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Osteoblast differentiation of human mesenchymal stem cells (hMSCs) is stimulated by 1α,25‐dihydroxycholecalciferol [1α,25(OH)2D3] and 25‐hydroxycholecalciferol [25(OH)D3]; the latter's effects require intracellular hydroxylation to 1α,25(OH)2D3. Thus, hMSCs are both a source of and target for 1α,25(OH)2D3. Megalin is a transmembrane receptor for serum d‐binding protein (DBP) in kidney cells and is required for uptake of the 25(OH)D3‐DBP complex. We tested the hypothesis that megalin is required for D actions in hMSCs with cells from surgically discarded marrow for RT‐PCR, for effects of 25(OH)D3 and 1α,25(OH)2D3, for 1α,25(OH)2D3 biosynthesis, for osteoblastogenesis, and for small interfering RNA for megalin (si‐Meg) and control (si‐Ctr). In hMSCs with high constitutive megalin expression, both 1α,25(OH)2D3 and 25(OH)D3 stimulated osteoblastogenesis (P < 0.05), but only 1α,25(OH)2D3 did so in hMSCs with lower megalin (lo‐Meg, P < 0.001) or in si‐Meg cells (P < 0.05). In addition, 1α,25(OH)2D3 biosynthesis was significantly lower in lo‐Meg (46%, P = 0.034) and in si‐Meg (23%, P < 0.001) than each control. Leptin significantly stimulated megalin expression 2.1‐fold in lo‐Meg cells (P < 0.01). These studies show that megalin is expressed in hMSCs and is required for the biosynthesis of 1α,25(OH)2D3 and for the 25(OH)D3/DBP complex to stimulate vitamin D receptor targets and osteoblastogenesis.—Gao, Y., Zhou, S., Luu, S., Glowacki, J. Megalin mediates 25‐hydroxyvitamin D3 actions in human mesenchymal stem cells. FASEB J. 33, 7684–7693 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Megalin mediates 25‐hydroxyvitamin D₃actions in human mesenchymal stem cells

et al. 2019

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“…Loss of this receptor in congenital or acquired diseases results in multiple organ dysfunctions, including forebrain malformation (holoprosencephaly) and the Donnai-Barrow/Facio-Oculo-Acustico-Renal syndrome characterized by a multifaceted phenotype including low-molecular-weight proteinuria [69] and renal reabsorption defects (renal Fanconi syndrome) [70]. Beydoun et al [71] also demonstrated that VDR and megalin gene variations can modify age-related cognitive decline among US adults.…”

Section: Megalin Cubilin and Vitamin D: A Synergy Into Proximal Tubumentioning

confidence: 99%

Protective Role of Vitamin D in Renal Tubulopathies

et al. 2020

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Vitamin D is tightly linked with renal tubular homeostasis: the mitochondria of proximal convoluted tubule cells are the production site of 1α,25-dihydroxyvitamin D3. Patients with renal impairment or tubular injury often suffer from chronic inflammation. This alteration comes from oxidative stress, acidosis, decreased clearance of inflammatory cytokines and stimulation of inflammatory factors. The challenge is to find the right formula for each patient to correctly modulate the landscape of treatment and preserve the essential functions of the organism without perturbating its homeostasis. The complexity of the counter-regulation mechanisms and the different axis involved in the Vitamin D equilibrium pose a major issue on Vitamin D as a potential effective anti-inflammatory drug. The therapeutic use of this compound should be able to inhibit the development of inflammation without interfering with normal homeostasis. Megalin-Cubilin-Amnionless and the FGF23-Klotho axis represent two Vitamin D-linked mechanisms that could modulate and ameliorate the damage response at the renal tubular level, balancing Vitamin D therapy with an effect potent enough to contrast the inflammatory cascades, but which avoids potential severe side effects.

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“…The overall structure of megalin resembles LDLR-related protein 1 (LRP1), and therefore, megalin is also known as LRP2 [17]. The very large extracellular domain allows megalin to bind multiple ligands [20], and until now, > 50 ligands for megalin have been described, including albumin, insulin, insulin-like growth factor, lipoproteins, and drugs like aprotinin and polymyxin B [18,21,22].…”

Section: What Is Megalin?mentioning

confidence: 99%

Megalin: a Novel Determinant of Renin-Angiotensin System Activity in the Kidney?

Sun

Danser

2020

Curr Hypertens Rep

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Purpose of Review Megalin is well known for its role in the reabsorption of proteins from the ultrafiltrate. Recent studies suggest that megalin also reabsorbs renin and angiotensinogen. Indeed, without megalin urinary renin and angiotensinogen levels massively increase, and even prorenin becomes detectable in urine. Recent Findings Intriguingly, megalin might also contribute to renal angiotensin production, as evidenced from studies in megalin knockout mice. This review discusses these topics critically, concluding that urinary renin-angiotensin system components reflect diminished reabsorption rather than release from renal tissue sites and that alterations in renal renin levels or megalin-dependent signaling need to be ruled out before concluding that angiotensin production at renal tissue sites is truly megalin dependent. Summary Future studies should evaluate megalin-mediated renin/angiotensinogen transcytosis (allowing interstitial angiotensin generation), and determine whether megalin prefers prorenin over renin, thus explaining why urine normally contains no prorenin.

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Endocytic receptor LRP2/megalin—of holoprosencephaly and renal Fanconi syndrome

Cited by 38 publications

References 105 publications

Megalin mediates 25‐hydroxyvitamin D₃actions in human mesenchymal stem cells

Megalin mediates 25‐hydroxyvitamin D₃actions in human mesenchymal stem cells

Protective Role of Vitamin D in Renal Tubulopathies

Megalin: a Novel Determinant of Renin-Angiotensin System Activity in the Kidney?

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Endocytic receptor LRP2/megalin—of holoprosencephaly and renal Fanconi syndrome

Cited by 38 publications

References 105 publications

Megalin mediates 25‐hydroxyvitamin D3actions in human mesenchymal stem cells

Megalin mediates 25‐hydroxyvitamin D3actions in human mesenchymal stem cells

Protective Role of Vitamin D in Renal Tubulopathies

Megalin: a Novel Determinant of Renin-Angiotensin System Activity in the Kidney?

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Megalin mediates 25‐hydroxyvitamin D₃actions in human mesenchymal stem cells

Megalin mediates 25‐hydroxyvitamin D₃actions in human mesenchymal stem cells