Megalin, a multi-ligand endocytic receptor, and its participation in renal function and diseases: A review

Elsakka, Elsayed G.E.; Mokhtar, Mahmoud Mohamed; Hegazy, Maghawry; Ismail, Ahmed; Doghish, Ahmed S.

doi:10.1016/j.lfs.2022.120923

Cited by 54 publications

(10 citation statements)

References 135 publications

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“…ClC-5's unique role in megalin and cubilin-mediated endocytosis was demonstrated when ClC-5 knockout animals showed lower endocytosis of megalin/cubilin ligands, suggesting that ClC-5 is required for megalin and cubilin trafficking in proximal tubules. Moreover, the acidification of endosomes enhances dissociation between megalin, and its ligand, followed by megalin recycling to the brush border membrane [1,7,22]. Our findings showed that shikonin inhibited megalin/cubilin complex expression in gentamicin-treated rats in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 59%

“…In the present study, megalin, cubilin, and CLC-5 renal levels and mRNA expressions were elevated in gentamicin-treated rats; however, the NHE3 level and mRNA expression were reduced in the gentamicin-treated group. The increased expression of the megalin/cubilin complex increased the proximal tubular uptake of gentamicin and its accumulation in the Golgi apparatus and lysosomes, which, when reached at a particular concentration, induces their rupture with the release of its content into the cytoplasm, causing oxidative stress and apoptosis and thus promoting the development and progression of renal injury [22]. On the other hand, treatment with shikonin significantly and dose-dependently decreased megalin/cubilin complex expression, which decreased gentamicin accumulation in proximal tubular cells and protected the kidneys from damage caused by gentamicin.…”

Section: Discussionmentioning

confidence: 99%

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Shikonin Alleviates Gentamicin-Induced Renal Injury in Rats by Targeting Renal Endocytosis, SIRT1/Nrf2/HO-1, TLR-4/NF-κB/MAPK, and PI3K/Akt Cascades

et al. 2023

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Gentamicin causes kidney injury due to its accumulation in proximal tubule epithelial cells via the megalin/cubilin/CLC-5 complex. Recently, shikonin has been shown to have potential anti-inflammatory, antioxidant, antimicrobial, and chloride channel-inhibiting effects. The current study investigated the alleviation of gentamicin-induced renal injury by shikonin while preserving its bactericidal effect. Nine-week-old Wistar rats were administered 6.25, 12.5, and 25 mg/kg/day shikonin orally, one hour after the i.p. injection of 100 mg/kg/day gentamicin for seven days. Shikonin significantly and dose-dependently alleviated gentamicin-induced renal injury, as revealed by restoring normal kidney function and histological architecture. Furthermore, shikonin restored renal endocytic function, as indicated by suppressing the elevated renal megalin, cubilin, and CLC-5 and enhancing the reduced NHE3 levels and mRNA expressions induced by gentamicin. These potentials could be attributed to the modulation of the renal SIRT1/Nrf2/HO-1, TLR-4/NF-κB/MAPK, and PI3K/Akt cascades, which enhanced the renal antioxidant system and suppressed renal inflammation and apoptosis, as indicated by enhancements of SIRT1, Nrf2, HO-1, GSH, SOD, TAC, Iκb-α, Bcl-2, PI3K, and Akt levels and mRNA expressions, with reduction of TLR-4, NF-κB, MAPK, IL-1β, TNF-α, MDA, iNOS, NO, cytochrome c, caspase-3, Bax levels, and Bax/Bcl-2 ratio. Therefore, shikonin is a promising therapeutic agent for alleviating gentamicin-induced renal injury.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Shikonin Alleviates Gentamicin-Induced Renal Injury in Rats by Targeting Renal Endocytosis, SIRT1/Nrf2/HO-1, TLR-4/NF-κB/MAPK, and PI3K/Akt Cascades

et al. 2023

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“…As a result of Cd-induced oxidative damage to carrier proteins and mitochondria ( 181 ), Fanconi syndrome is characterized by clinically visible defects in protein, bicarbonate, phosphate, and amino acid reabsorption ( 200 , 201 ). Approximately thirty percent of body Cd is accumulated in kidney tubule segments, with tubular injury proportional to the amount of Cd that is not bound to metallothionein ( 202 , 203 ). It was concluded that Cd toxicity damages the kidney through oxidative stress.…”

Section: Heavy Metals: Their Toxicity Mechanism and Effectsmentioning

confidence: 99%

A review of important heavy metals toxicity with special emphasis on nephrotoxicity and its management in cattle

Tahir

Alkheraije

2023

Front. Vet. Sci.

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Toxicity with heavy metals has proven to be a significant hazard with several health problems linked to it. Heavy metals bioaccumulate in living organisms, pollute the food chain, and possibly threaten the health of animals. Many industries, fertilizers, traffic, automobile, paint, groundwater, and animal feed are sources of contamination of heavy metals. Few metals, such as aluminum (Al), may be eliminated by the elimination processes, but other metals like lead (Pb), arsenic (As), and cadmium (Ca) accumulate in the body and food chain, leading to chronic toxicity in animals. Even if these metals have no biological purpose, their toxic effects are still present in some form that is damaging to the animal body and its appropriate functioning. Cadmium (Cd) and Pb have negative impacts on a number of physiological and biochemical processes when exposed to sub-lethal doses. The nephrotoxic effects of Pb, As, and Cd are well known, and high amounts of naturally occurring environmental metals as well as occupational populations with high exposures have an adverse relationship between kidney damage and toxic metal exposure. Metal toxicity is determined by the absorbed dosage, the route of exposure, and the duration of exposure, whether acute or chronic. This can lead to numerous disorders and can also result in excessive damage due to oxidative stress generated by free radical production. Heavy metals concentration can be decreased through various procedures including bioremediation, pyrolysis, phytoremediation, rhizofiltration, biochar, and thermal process. This review discusses few heavy metals, their toxicity mechanisms, and their health impacts on cattle with special emphasis on the kidneys.

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“…Larger peptides and proteins are transported from the urine by the multi-ligand endocytic megalin receptor complex localized at the apical membrane of the proximal renal tubules. Megalin (LRP2) is a large glycoprotein, a member of the low-density lipoprotein receptor family, and is abundantly expressed in the proximal kidney tubules and several other absorptive epithelia [ 14 , 15 ]. The megalin system mediates the transport of peptides and proteins such as albumin, plasminogen, polybasic drugs, or low-molecular-weight polypeptides such as insulin and angiotensin II [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…Radiolabeled albumin and DMSA (dimercaptosuccinate) were selected as markers of proximal tubule endocytic activity. Both compounds are known as substrates of the megalin endocytic receptor [ 14 , 17 ]. [ 99m Tc]Tc-MAG3 (mercaptoacetylglycylglycylglycine) is transported into renal cells via an energy-dependent transport system for organic anions [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Validation of Freshly Isolated Rat Renal Cells as a Tool for Preclinical Assessment of Radiolabeled Receptor-Specific Peptide Uptake in the Kidney

et al. 2023

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The synthetic analogs of regulatory peptides radiolabeled with adequate radionuclides are perspective tools in nuclear medicine. However, undesirable uptake and retention in the kidney limit their application. Specific in vitro methods are used to evaluate undesirable renal accumulation. Therefore, we investigated the usefulness of freshly isolated rat renal cells for evaluating renal cellular uptake of receptor-specific peptide analogs. Special attention was given to megalin as this transport system is an important contributor to the active renal uptake of the peptides. Freshly isolated renal cells were obtained from native rat kidneys by the collagenase method. Compounds with known accumulation in renal cells were used to verify the viability of cellular transport systems. Megalin expressions in isolated rat renal cells were compared to two other potential renal cell models by Western blotting. Specific tubular cell markers were used to confirm the presence of proximal tubular cells expressing megalin in isolated rat renal cell preparations by immunohistochemistry. Colocalization experiments on isolated rat kidney cells confirmed the presence of proximal tubular cells bearing megalin in preparations. The applicability of the method was tested by an accumulation study with several analogs of somatostatin and gastrin labeled with indium-111 or lutetium-177. Therefore, isolated rat renal cells may be an effective screening tool for in vitro analyses of renal uptake and comparative renal accumulation studies of radiolabeled peptides or other radiolabeled compounds with potential nephrotoxicity.

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Megalin, a multi-ligand endocytic receptor, and its participation in renal function and diseases: A review

Cited by 54 publications

References 135 publications

Shikonin Alleviates Gentamicin-Induced Renal Injury in Rats by Targeting Renal Endocytosis, SIRT1/Nrf2/HO-1, TLR-4/NF-κB/MAPK, and PI3K/Akt Cascades

Shikonin Alleviates Gentamicin-Induced Renal Injury in Rats by Targeting Renal Endocytosis, SIRT1/Nrf2/HO-1, TLR-4/NF-κB/MAPK, and PI3K/Akt Cascades

A review of important heavy metals toxicity with special emphasis on nephrotoxicity and its management in cattle

Validation of Freshly Isolated Rat Renal Cells as a Tool for Preclinical Assessment of Radiolabeled Receptor-Specific Peptide Uptake in the Kidney

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