Interference with megalin expression/endocytic function by montelukast mitigates gentamicin nephrotoxicity: Downregulation of ClC-5 expression
Megalin receptor-mediated endocytosis participates a crucial role in gentamicin (GM) uptake, accumulation, and toxicity. In this study, we investigated the potential effects of montelukast (MLK) on megalin expression/endocytic function against GM nephrotoxicity. Male Wistar rats were administered GM...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-02-01
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| Series: | Saudi Pharmaceutical Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1319016421002620 |
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| author | Amany A. Azouz Dina A. Hanna Ali A. Abo-Saif Basim Anwar Shehata Messiha |
| author_facet | Amany A. Azouz Dina A. Hanna Ali A. Abo-Saif Basim Anwar Shehata Messiha |
| author_sort | Amany A. Azouz |
| collection | DOAJ |
| description | Megalin receptor-mediated endocytosis participates a crucial role in gentamicin (GM) uptake, accumulation, and toxicity. In this study, we investigated the potential effects of montelukast (MLK) on megalin expression/endocytic function against GM nephrotoxicity. Male Wistar rats were administered GM (120 mg/kg; i.p.) daily in divided doses along 4 hr; 30 mg/kg/hr; for 7 days. MLK (30 mg/kg/day) was orally administered 7 days before and then concurrently with GM. The protein expressions of megalin and chloride channel-5 (ClC-5); one of the essential regulators of megalin endocytic function; were determined by Western blotting. Besides, the endocytic function of megalin was evaluated by the uptake of bovine serum albumin labeled with fluorescein isothiocyanate (FITC-BSA) into proximal tubular epithelial cells. Moreover, kidney function biomarkers (Cr, BUN, GFR, KIM-1, cystatin-C) and apoptosis markers (p-AKT1, cleaved caspase-3) were estimated. Co-treatment with MLK downregulated ClC-5 expression leading to reduced recycling of megalin to the plasma membrane, reduced expression, and so impaired endocytic function that was evidenced by reduced uptake of FITC-BSA in proximal tubular epithelial cells. The protein expression of the apoptotic executioner cleaved caspase-3 was significantly reduced, while that of the antiapoptotic p-AKT1 was elevated. These results were confirmed by the improvement of kidney functions and histological findings. Our data suggest that MLK could interfere with megalin expression/endocytic function that could be attributed to downregulation of ClC-5 protein expression. That eventually reduces renal cell apoptosis and improves kidney functions after GM administration without affecting the antibacterial activity of GM. Therefore, reduced expression of ClC-5 and interference with megalin expression/endocytic function by MLK could be an effective strategy against GM nephrotoxicity. |
| first_indexed | 2024-12-19T21:18:56Z |
| format | Article |
| id | doaj.art-a69514b6decf458ba0285b7087920df0 |
| institution | Directory Open Access Journal |
| issn | 1319-0164 |
| language | English |
| last_indexed | 2024-12-19T21:18:56Z |
| publishDate | 2022-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Saudi Pharmaceutical Journal |
| spelling | doaj.art-a69514b6decf458ba0285b7087920df02022-12-21T20:05:17ZengElsevierSaudi Pharmaceutical Journal1319-01642022-02-01302150161Interference with megalin expression/endocytic function by montelukast mitigates gentamicin nephrotoxicity: Downregulation of ClC-5 expressionAmany A. Azouz0Dina A. Hanna1Ali A. Abo-Saif2Basim Anwar Shehata Messiha3Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; Corresponding author.Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, EgyptDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, EgyptDepartment of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, EgyptMegalin receptor-mediated endocytosis participates a crucial role in gentamicin (GM) uptake, accumulation, and toxicity. In this study, we investigated the potential effects of montelukast (MLK) on megalin expression/endocytic function against GM nephrotoxicity. Male Wistar rats were administered GM (120 mg/kg; i.p.) daily in divided doses along 4 hr; 30 mg/kg/hr; for 7 days. MLK (30 mg/kg/day) was orally administered 7 days before and then concurrently with GM. The protein expressions of megalin and chloride channel-5 (ClC-5); one of the essential regulators of megalin endocytic function; were determined by Western blotting. Besides, the endocytic function of megalin was evaluated by the uptake of bovine serum albumin labeled with fluorescein isothiocyanate (FITC-BSA) into proximal tubular epithelial cells. Moreover, kidney function biomarkers (Cr, BUN, GFR, KIM-1, cystatin-C) and apoptosis markers (p-AKT1, cleaved caspase-3) were estimated. Co-treatment with MLK downregulated ClC-5 expression leading to reduced recycling of megalin to the plasma membrane, reduced expression, and so impaired endocytic function that was evidenced by reduced uptake of FITC-BSA in proximal tubular epithelial cells. The protein expression of the apoptotic executioner cleaved caspase-3 was significantly reduced, while that of the antiapoptotic p-AKT1 was elevated. These results were confirmed by the improvement of kidney functions and histological findings. Our data suggest that MLK could interfere with megalin expression/endocytic function that could be attributed to downregulation of ClC-5 protein expression. That eventually reduces renal cell apoptosis and improves kidney functions after GM administration without affecting the antibacterial activity of GM. Therefore, reduced expression of ClC-5 and interference with megalin expression/endocytic function by MLK could be an effective strategy against GM nephrotoxicity.http://www.sciencedirect.com/science/article/pii/S1319016421002620Gentamicin endocytosisMegalinChloride channel-5MontelukastApoptosis |
| spellingShingle | Amany A. Azouz Dina A. Hanna Ali A. Abo-Saif Basim Anwar Shehata Messiha Interference with megalin expression/endocytic function by montelukast mitigates gentamicin nephrotoxicity: Downregulation of ClC-5 expression Saudi Pharmaceutical Journal Gentamicin endocytosis Megalin Chloride channel-5 Montelukast Apoptosis |
| title | Interference with megalin expression/endocytic function by montelukast mitigates gentamicin nephrotoxicity: Downregulation of ClC-5 expression |
| title_full | Interference with megalin expression/endocytic function by montelukast mitigates gentamicin nephrotoxicity: Downregulation of ClC-5 expression |
| title_fullStr | Interference with megalin expression/endocytic function by montelukast mitigates gentamicin nephrotoxicity: Downregulation of ClC-5 expression |
| title_full_unstemmed | Interference with megalin expression/endocytic function by montelukast mitigates gentamicin nephrotoxicity: Downregulation of ClC-5 expression |
| title_short | Interference with megalin expression/endocytic function by montelukast mitigates gentamicin nephrotoxicity: Downregulation of ClC-5 expression |
| title_sort | interference with megalin expression endocytic function by montelukast mitigates gentamicin nephrotoxicity downregulation of clc 5 expression |
| topic | Gentamicin endocytosis Megalin Chloride channel-5 Montelukast Apoptosis |
| url | http://www.sciencedirect.com/science/article/pii/S1319016421002620 |
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