Rapamycin treatment induces tubular proteinuria: role of megalin-mediated protein reabsorption
Introduction: Rapamycin is an immunosuppressor that acts by inhibiting the serine/threonine kinase mechanistic target of rapamycin complex 1. Therapeutic use of rapamycin is limited by its adverse effects. Proteinuria is an important marker of kidney damage and a risk factor for kidney diseases prog...
| Asıl Yazarlar: | , , , , , , , |
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| Materyal Türü: | Makale |
| Dil: | English |
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Frontiers Media S.A.
2023-07-01
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| Seri Bilgileri: | Frontiers in Pharmacology |
| Konular: | |
| Online Erişim: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1194816/full |
| _version_ | 1827906232795529216 |
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| author | Rodrigo A. S. Peres Diogo B. Peruchetti Rodrigo P. Silva-Aguiar Douglas E. Teixeira Carlos P. Gomes Carlos P. Gomes Christina M. Takiya Ana Acacia S. Pinheiro Ana Acacia S. Pinheiro Celso Caruso-Neves Celso Caruso-Neves Celso Caruso-Neves |
| author_facet | Rodrigo A. S. Peres Diogo B. Peruchetti Rodrigo P. Silva-Aguiar Douglas E. Teixeira Carlos P. Gomes Carlos P. Gomes Christina M. Takiya Ana Acacia S. Pinheiro Ana Acacia S. Pinheiro Celso Caruso-Neves Celso Caruso-Neves Celso Caruso-Neves |
| author_sort | Rodrigo A. S. Peres |
| collection | DOAJ |
| description | Introduction: Rapamycin is an immunosuppressor that acts by inhibiting the serine/threonine kinase mechanistic target of rapamycin complex 1. Therapeutic use of rapamycin is limited by its adverse effects. Proteinuria is an important marker of kidney damage and a risk factor for kidney diseases progression and has been reported in patients and animal models treated with rapamycin. However, the mechanism underlying proteinuria induced by rapamycin is still an open matter. In this work, we investigated the effects of rapamycin on parameters of renal function and structure and on protein handling by proximal tubule epithelial cells (PTECs).Methods: Healthy BALB/c mice were treated with 1.5 mg/kg rapamycin by oral gavage for 1, 3, or 7 days. At the end of each treatment, the animals were kept in metabolic cages and renal function and structural parameters were analyzed. LLC-PK1 cell line was used as a model of PTECs to test specific effect of rapamycin.Results: Rapamycin treatment did not change parameters of glomerular structure and function. Conversely, there was a transient increase in 24-h proteinuria, urinary protein to creatinine ratio (UPCr), and albuminuria in the groups treated with rapamycin. In accordance with these findings, rapamycin treatment decreased albumin-fluorescein isothiocyanate uptake in the renal cortex. This effect was associated with reduced brush border expression and impaired subcellular distribution of megalin in PTECs. The effect of rapamycin seems to be specific for albumin endocytosis machinery because it did not modify renal sodium handling or (Na++K+)ATPase activity in BALB/c mice and in the LLC-PK1 cell line. A positive Pearson correlation was found between megalin expression and albumin uptake while an inverse correlation was shown between albumin uptake and UPCr or 24-h proteinuria. Despite its effect on albumin handling in PTECs, rapamycin treatment did not induce tubular injury measured by interstitial space and collagen deposition.Conclusion: These findings suggest that proteinuria induced by rapamycin could have a tubular rather than a glomerular origin. This effect involves a specific change in protein endocytosis machinery. Our results open new perspectives on understanding the undesired effect of proteinuria generated by rapamycin. |
| first_indexed | 2024-03-13T00:53:37Z |
| format | Article |
| id | doaj.art-db2a32c3f1b64a25abd3824d7ab4b217 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-13T00:53:37Z |
| publishDate | 2023-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-db2a32c3f1b64a25abd3824d7ab4b2172023-07-07T07:42:18ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-07-011410.3389/fphar.2023.11948161194816Rapamycin treatment induces tubular proteinuria: role of megalin-mediated protein reabsorptionRodrigo A. S. Peres0Diogo B. Peruchetti1Rodrigo P. Silva-Aguiar2Douglas E. Teixeira3Carlos P. Gomes4Carlos P. Gomes5Christina M. Takiya6Ana Acacia S. Pinheiro7Ana Acacia S. Pinheiro8Celso Caruso-Neves9Celso Caruso-Neves10Celso Caruso-Neves11Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilDepartment of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, BrazilCarlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilCarlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilClementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilSchool of Medicine and Surgery, Federal University of the State of Rio de Janeiro, Rio de Janeiro, BrazilCarlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilCarlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilRio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE/FAPERJ, Rio de Janeiro, BrazilCarlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, BrazilRio de Janeiro Innovation Network in Nanosystems for Health-NanoSAÚDE/FAPERJ, Rio de Janeiro, BrazilNational Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, BrazilIntroduction: Rapamycin is an immunosuppressor that acts by inhibiting the serine/threonine kinase mechanistic target of rapamycin complex 1. Therapeutic use of rapamycin is limited by its adverse effects. Proteinuria is an important marker of kidney damage and a risk factor for kidney diseases progression and has been reported in patients and animal models treated with rapamycin. However, the mechanism underlying proteinuria induced by rapamycin is still an open matter. In this work, we investigated the effects of rapamycin on parameters of renal function and structure and on protein handling by proximal tubule epithelial cells (PTECs).Methods: Healthy BALB/c mice were treated with 1.5 mg/kg rapamycin by oral gavage for 1, 3, or 7 days. At the end of each treatment, the animals were kept in metabolic cages and renal function and structural parameters were analyzed. LLC-PK1 cell line was used as a model of PTECs to test specific effect of rapamycin.Results: Rapamycin treatment did not change parameters of glomerular structure and function. Conversely, there was a transient increase in 24-h proteinuria, urinary protein to creatinine ratio (UPCr), and albuminuria in the groups treated with rapamycin. In accordance with these findings, rapamycin treatment decreased albumin-fluorescein isothiocyanate uptake in the renal cortex. This effect was associated with reduced brush border expression and impaired subcellular distribution of megalin in PTECs. The effect of rapamycin seems to be specific for albumin endocytosis machinery because it did not modify renal sodium handling or (Na++K+)ATPase activity in BALB/c mice and in the LLC-PK1 cell line. A positive Pearson correlation was found between megalin expression and albumin uptake while an inverse correlation was shown between albumin uptake and UPCr or 24-h proteinuria. Despite its effect on albumin handling in PTECs, rapamycin treatment did not induce tubular injury measured by interstitial space and collagen deposition.Conclusion: These findings suggest that proteinuria induced by rapamycin could have a tubular rather than a glomerular origin. This effect involves a specific change in protein endocytosis machinery. Our results open new perspectives on understanding the undesired effect of proteinuria generated by rapamycin.https://www.frontiersin.org/articles/10.3389/fphar.2023.1194816/fullrapamycinproximal tubulemegalinprotein reabsorptionproteinuria |
| spellingShingle | Rodrigo A. S. Peres Diogo B. Peruchetti Rodrigo P. Silva-Aguiar Douglas E. Teixeira Carlos P. Gomes Carlos P. Gomes Christina M. Takiya Ana Acacia S. Pinheiro Ana Acacia S. Pinheiro Celso Caruso-Neves Celso Caruso-Neves Celso Caruso-Neves Rapamycin treatment induces tubular proteinuria: role of megalin-mediated protein reabsorption Frontiers in Pharmacology rapamycin proximal tubule megalin protein reabsorption proteinuria |
| title | Rapamycin treatment induces tubular proteinuria: role of megalin-mediated protein reabsorption |
| title_full | Rapamycin treatment induces tubular proteinuria: role of megalin-mediated protein reabsorption |
| title_fullStr | Rapamycin treatment induces tubular proteinuria: role of megalin-mediated protein reabsorption |
| title_full_unstemmed | Rapamycin treatment induces tubular proteinuria: role of megalin-mediated protein reabsorption |
| title_short | Rapamycin treatment induces tubular proteinuria: role of megalin-mediated protein reabsorption |
| title_sort | rapamycin treatment induces tubular proteinuria role of megalin mediated protein reabsorption |
| topic | rapamycin proximal tubule megalin protein reabsorption proteinuria |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1194816/full |
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