Chronic dehydration induces injury pathways in rats, but does not mimic histopathology of chronic interstitial nephritis in agricultural communities
Abstract CINAC-patients present renal proximal tubular cell lysosomal lesions which are also observed in patients experiencing calcineurin inhibitor (CNI) nephrotoxicity, suggesting that CINAC is a toxin-induced nephropathy. An alternative hypothesis advocates chronic dehydration as a major etiologi...
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| Format: | Article |
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Nature Portfolio
2023-10-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-43567-z |
| _version_ | 1827711461476007936 |
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| author | Gerd Schreurs Stuart Maudsley Cynthia Nast Marleen Praet Sylvina Da Silva Fernandes Peter Boor Patrick D’Haese Marc E. De Broe Benjamin A. Vervaet |
| author_facet | Gerd Schreurs Stuart Maudsley Cynthia Nast Marleen Praet Sylvina Da Silva Fernandes Peter Boor Patrick D’Haese Marc E. De Broe Benjamin A. Vervaet |
| author_sort | Gerd Schreurs |
| collection | DOAJ |
| description | Abstract CINAC-patients present renal proximal tubular cell lysosomal lesions which are also observed in patients experiencing calcineurin inhibitor (CNI) nephrotoxicity, suggesting that CINAC is a toxin-induced nephropathy. An alternative hypothesis advocates chronic dehydration as a major etiological factor for CINAC. Here, we evaluated histological and molecular changes in dehydrated versus toxin exposed rats. Wistar rats were divided in 3 groups. Group 1 (n = 6) had free access to drinking water (control group). Group 2 (n = 8) was water deprived for 10 h per 24 h, 5 days/week and placed in an incubator (37 °C) for 30 min/h during water deprivation. Group 3 (n = 8) underwent daily oral gavage with cyclosporine (40 mg/kg body weight). After 28 days, renal function, histopathology and proteomic signatures were analysed. Cyclosporine-treated rats developed focal regions of atrophic proximal tubules with associated tubulo-interstitial fibrosis. PASM staining revealed enlarged argyrophilic granules in affected proximal tubules, identified as lysosomes by immunofluorescent staining. Electron microscopy confirmed the enlarged and dysmorphic phenotype of the lysosomes. Overall, these kidney lesions resemble those that have been previously documented in farmers with CINAC. Dehydration resulted in none of the above histopathological features. Proteomic analysis revealed that dehydration and cyclosporine both induce injury pathways, yet of a clear distinct nature with a signature of toxicity only for the cyclosporine group. In conclusion, both cyclosporine and dehydration are injurious to the kidney. However, dehydration alone does not result in kidney histopathology as observed in CINAC patients, whereas cyclosporine administration does. The histopathological analogy between CINAC and calcineurin inhibitor nephrotoxicity in rats and humans supports the involvement of an as-yet-unidentified environmental toxin in CINAC etiology. |
| first_indexed | 2024-03-10T17:54:53Z |
| format | Article |
| id | doaj.art-6be3755f172742d2a584a36cadf387ba |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-10T17:54:53Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-6be3755f172742d2a584a36cadf387ba2023-11-20T09:13:40ZengNature PortfolioScientific Reports2045-23222023-10-0113111410.1038/s41598-023-43567-zChronic dehydration induces injury pathways in rats, but does not mimic histopathology of chronic interstitial nephritis in agricultural communitiesGerd Schreurs0Stuart Maudsley1Cynthia Nast2Marleen Praet3Sylvina Da Silva Fernandes4Peter Boor5Patrick D’Haese6Marc E. De Broe7Benjamin A. Vervaet8Laboratory of Pathophysiology, University of AntwerpReceptor Biology Lab, Department of Biomedical Science, University of AntwerpCedars-Sinai Medical CenterDepartment of Pathology, Ghent University HospitalLaboratory of Pathophysiology, University of AntwerpInstitute of Pathology, Electron Microscopy Facility and Division of Nephrology and Immunology, RWTH Aachen University HospitalLaboratory of Pathophysiology, University of AntwerpLaboratory of Pathophysiology, University of AntwerpLaboratory of Pathophysiology, University of AntwerpAbstract CINAC-patients present renal proximal tubular cell lysosomal lesions which are also observed in patients experiencing calcineurin inhibitor (CNI) nephrotoxicity, suggesting that CINAC is a toxin-induced nephropathy. An alternative hypothesis advocates chronic dehydration as a major etiological factor for CINAC. Here, we evaluated histological and molecular changes in dehydrated versus toxin exposed rats. Wistar rats were divided in 3 groups. Group 1 (n = 6) had free access to drinking water (control group). Group 2 (n = 8) was water deprived for 10 h per 24 h, 5 days/week and placed in an incubator (37 °C) for 30 min/h during water deprivation. Group 3 (n = 8) underwent daily oral gavage with cyclosporine (40 mg/kg body weight). After 28 days, renal function, histopathology and proteomic signatures were analysed. Cyclosporine-treated rats developed focal regions of atrophic proximal tubules with associated tubulo-interstitial fibrosis. PASM staining revealed enlarged argyrophilic granules in affected proximal tubules, identified as lysosomes by immunofluorescent staining. Electron microscopy confirmed the enlarged and dysmorphic phenotype of the lysosomes. Overall, these kidney lesions resemble those that have been previously documented in farmers with CINAC. Dehydration resulted in none of the above histopathological features. Proteomic analysis revealed that dehydration and cyclosporine both induce injury pathways, yet of a clear distinct nature with a signature of toxicity only for the cyclosporine group. In conclusion, both cyclosporine and dehydration are injurious to the kidney. However, dehydration alone does not result in kidney histopathology as observed in CINAC patients, whereas cyclosporine administration does. The histopathological analogy between CINAC and calcineurin inhibitor nephrotoxicity in rats and humans supports the involvement of an as-yet-unidentified environmental toxin in CINAC etiology.https://doi.org/10.1038/s41598-023-43567-z |
| spellingShingle | Gerd Schreurs Stuart Maudsley Cynthia Nast Marleen Praet Sylvina Da Silva Fernandes Peter Boor Patrick D’Haese Marc E. De Broe Benjamin A. Vervaet Chronic dehydration induces injury pathways in rats, but does not mimic histopathology of chronic interstitial nephritis in agricultural communities Scientific Reports |
| title | Chronic dehydration induces injury pathways in rats, but does not mimic histopathology of chronic interstitial nephritis in agricultural communities |
| title_full | Chronic dehydration induces injury pathways in rats, but does not mimic histopathology of chronic interstitial nephritis in agricultural communities |
| title_fullStr | Chronic dehydration induces injury pathways in rats, but does not mimic histopathology of chronic interstitial nephritis in agricultural communities |
| title_full_unstemmed | Chronic dehydration induces injury pathways in rats, but does not mimic histopathology of chronic interstitial nephritis in agricultural communities |
| title_short | Chronic dehydration induces injury pathways in rats, but does not mimic histopathology of chronic interstitial nephritis in agricultural communities |
| title_sort | chronic dehydration induces injury pathways in rats but does not mimic histopathology of chronic interstitial nephritis in agricultural communities |
| url | https://doi.org/10.1038/s41598-023-43567-z |
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