Decreased urinary excretion of the ectodomain form of megalin (A-megalin) in children with OCRL gene mutations

Suruda, Chikushi; Tsuji, Shoji; Yamanouchi, Sohsaku; Kimata, Takahisa; Nguyen, Huan Thanh; Kurosawa, Hiroyuki; Hirayama, Yoshiaki; Tsukaguchi, Hiroyasu; Saito, Akihiko

doi:10.1007/s00467-016-3535-x

Cited by 10 publications

(17 citation statements)

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“…These results were similar to those of a previous study that investigated urinary A-megalin in diabetic patients, in which urinary A-megalin levels were found to be increased in diabetic patients with normo- and microalbuminuria, but not in those with macroalbuminuria [21]. Although urinary A-megalin excretion might be elevated by distinct mechanisms, as noted above [25, 26], the clinical importance of that increase remains to be investigated further.…”

Section: Discussionsupporting

confidence: 79%

“…Urinary C-megalin/Cr was also found to be increased via exocytosis in association with megalin-mediated quantitative or qualitative protein metabolic load to the endo-lysosomal system of PTECs in residual functional nephrons [24]. Although it has been proposed that urinary A-megalin excretion might be increased by accelerated intracellular recycling [25] and regulated intramembrane proteolysis of megalin [26], its clinical relevance remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

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Urinary Iron Excretion is Associated with Urinary Full-Length Megalin and Renal Oxidative Stress in Chronic Kidney Disease

Nakatani

Ishimura

et al. 2018

Kidney Blood Press Res

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Background/Aims: Megalin mediates the uptake of glomerular-filtered iron in the proximal tubules. Urinary full length megalin (C-megalin) excretion has been found to be increased in association with megalin-mediated metabolic load to the endo-lysosomal system in proximal tubular epithelial cells (PTECs) of residual nephrons. In the present study, we investigated the association between urinary iron and C-megalin in chronic kidney disease (CKD) patients, and the possible harmful effect of iron in renal tubules. Methods: Urinary levels of iron and C-megalin were measured in 63 CKD patients using automatic absorption spectrometry and a recently-established sandwich ELISA, respectively. Results: Although both urinary C-megalin and urinary total protein levels were correlated with urinary iron (C-megalin: ρ = 0.574, p <0.001; total protein: ρ = 0.500, p <0.001, respectively), urinary C-megalin alone emerged as an independent factor positively associated with urinary iron (β = 0.520, p <0.001) (R² = 0.75, p <0.001). Furthermore, urinary iron was significantly and positively associated with urinary 8-hydroxydeoxyguanosine, an oxidative stress marker, while no association with other markers of renal tubular injury, i.e., β₂-microglobulin and N-acetyl-β-D-glucosaminidase, was noted. Conclusions: Our findings suggest that renal iron handling may be associated with megalin-mediated endo-lysosomal metabolic load in PTECs of residual nephrons and oxidative stress in renal tubules.

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Section: Discussionsupporting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Urinary Iron Excretion is Associated with Urinary Full-Length Megalin and Renal Oxidative Stress in Chronic Kidney Disease

Nakatani

Ishimura

et al. 2018

Kidney Blood Press Res

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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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“…opisali gen OCRL, którego mutacje stwierdzono u chorych z zespołem Lowe'a (Ls -Lowe syndrome). Jego produktem jest białko enzymatyczne 5-fosfataza 4,5--dwufosfo-fosfatydyloinozytolu, zidentyfikowane wewnątrzkomórkowo w aparacie Golgiego i odpowiadają-ce za polimeryzację aktyny [3,4]. Gen OCRL jest zlokalizowany na ramieniu długim chromosomu X w locus Xq25-26 i składa się z 24 eksonów [5].…”

Section: W St ę Punclassified

The oculocerebrorenal syndrome of Lowe – diagnostic and therapeutic problems in Polish health care system

Jarmoliński¹,

Zaniew²

2017

Ann. Acad. Med. Siles.

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Zespół oczno-mózgowo-nerkowy, opisany po raz pierwszy przez Lowe’a w 1952 roku, jest rzadkim defektem genetycznym (częstość 1 : 500 000), wywołanym mutacją w genie OCRL kodującym enzym 5-fosfatazę 4,5-dwufosfofosfatydyloinozytolu. Jest on zlokalizowany na chromosomie X (Xq25-26), a choroba dziedziczy się w sposób recesywny sprzężony z płcią. Typowymi objawami są: wrodzona zaćma, upośledzenie rozwoju umysłowego i tubulopatia proksymalna (wtórny zespół Fanconiego bez glukozurii) z wolno postępującym upośledzeniem czynności nerek, aż do schyłkowej ich niewydolności w 2–4 dekadzie życia. Inne objawy to: zaburzenia wzrastania, jaskra, woloocze, hipotonia mięśniowa, opóźnienie rozwoju motorycznego, dziwne zachowania (napady agresji i złości, ruchy mimowolne), wentrykulomegalia, przykurcze, artropatie, osteopenia, wnętrostwo, dysplazja zębów, torbiele skórne i skaza krwotoczna. Rozpoznanie wstępne można postawić na podstawie obrazu klinicznego z typową sekwencją pojawiania się objawów, z których początkowymi są zaćma, hipotonia z brakiem odruchów głębokich i białkomocz cewkowy. Potwierdzenie diagnozy stanowi badanie genetyczne, w którym stwierdza się jeden z ponad 200 znanych wariantów genu OCRL lub mutację de novo. Przedstawiono przypadek 2-letniego chłopca z obrazem klinicznym zespołu Lowe’a (wrodzona zaćma, hipotonia, opóźnienie rozwoju psychofizycznego i tubulopatia), diagnozowanego i leczonego w wielu ośrodkach. Po przekazaniu chorego pod opiekę powiatowego oddziału pediatrycznego w Międzyrzeczu rozpoznanie potwierdzono badaniem genetycznym, w którym wykazano hemizygotyczną punktową mutację w eksonie 13 OCRL (c.1351G > A); badanie wykonano dzięki uprzejmości prof. Michaela Ludwiga w Laboratorium Biologii Molekularnej Uniwersytetu w Bonn. Zwrócono uwagę na celowość wczesnego zgłaszania chorych z podejrzeniem zespołu Lowe’a do krajowego rejestru POLtube, co ułatwia dostęp do diagnostyki molekularnej.

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Decreased urinary excretion of the ectodomain form of megalin (A-megalin) in children with OCRL gene mutations

Cited by 10 publications

References 17 publications

Urinary Iron Excretion is Associated with Urinary Full-Length Megalin and Renal Oxidative Stress in Chronic Kidney Disease

Urinary Iron Excretion is Associated with Urinary Full-Length Megalin and Renal Oxidative Stress in Chronic Kidney Disease

Megalin mediates 25‐hydroxyvitamin D₃actions in human mesenchymal stem cells

The oculocerebrorenal syndrome of Lowe – diagnostic and therapeutic problems in Polish health care system

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Decreased urinary excretion of the ectodomain form of megalin (A-megalin) in children with OCRL gene mutations

Cited by 10 publications

References 17 publications

Urinary Iron Excretion is Associated with Urinary Full-Length Megalin and Renal Oxidative Stress in Chronic Kidney Disease

Urinary Iron Excretion is Associated with Urinary Full-Length Megalin and Renal Oxidative Stress in Chronic Kidney Disease

Megalin mediates 25‐hydroxyvitamin D3actions in human mesenchymal stem cells

The oculocerebrorenal syndrome of Lowe – diagnostic and therapeutic problems in Polish health care system

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Megalin mediates 25‐hydroxyvitamin D₃actions in human mesenchymal stem cells