Parp1 protects against Aag-dependent alkylation-induced nephrotoxicity in a sex-dependent manner
ephrotoxicity is a common toxic side-effect of chemotherapeutic alkylating agents. Although the base excision repair (BER) pathway is essential in repairing DNA alkylation damage, under certain conditions the initiation of BER produces toxic repair intermediates that damage healthy tissues. We have...
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| Format: | Article |
| Language: | en_US |
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Impact Journals/National Center for Biotechnology Information (U.S.)
2017
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| Online Access: | http://hdl.handle.net/1721.1/108345 https://orcid.org/0000-0002-7112-1454 |
| _version_ | 1811097168488955904 |
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| author | Bronson, Roderick T. Calvo, Jennifer Allocca, Mariacarmela Fake, Kimberly Muthupalani, Sureshkumar Corrigan, Joshua Samson, Leona D |
| author2 | Massachusetts Institute of Technology. Center for Environmental Health Sciences |
| author_facet | Massachusetts Institute of Technology. Center for Environmental Health Sciences Bronson, Roderick T. Calvo, Jennifer Allocca, Mariacarmela Fake, Kimberly Muthupalani, Sureshkumar Corrigan, Joshua Samson, Leona D |
| author_sort | Bronson, Roderick T. |
| collection | MIT |
| description | ephrotoxicity is a common toxic side-effect of chemotherapeutic alkylating agents. Although the base excision repair (BER) pathway is essential in repairing DNA alkylation damage, under certain conditions the initiation of BER produces toxic repair intermediates that damage healthy tissues. We have shown that the alkyladenine DNA glycosylase, Aag (a.k.a. Mpg), an enzyme that initiates BER, mediates alkylation-induced whole-animal lethality and cytotoxicity in the pancreas, spleen, retina, and cerebellum, but not in the kidney. Cytotoxicity in both wild-type and Aag-transgenic mice (AagTg) was abrogated in the absence of Poly(ADP-ribose) polymerase-1 (Parp1). Here we report that Parp1-deficient mice expressing increased Aag (AagTg/Parp1-/-) develop sex-dependent kidney failure upon exposure to the alkylating agent, methyl methanesulfonate (MMS), and suffer increased whole-animal lethality compared to AagTg and wild-type mice. Macroscopic, histological, electron microscopic and immunohistochemical analyses revealed morphological kidney damage including dilated tubules, proteinaceous casts, vacuolation, collapse of the glomerular tuft, and deterioration of podocyte structure. Moreover, mice exhibited clinical signs of kidney disease indicating functional damage, including elevated blood nitrogen urea and creatinine, hypoproteinemia and proteinuria. Pharmacological Parp inhibition in AagTg mice also resulted in sensitivity to MMS-induced nephrotoxicity. These findings provide in vivo evidence that Parp1 modulates Aag-dependent MMS-induced nephrotoxicity in a sex-dependent manner and highlight the critical roles that Aag-initiated BER and Parp1 may play in determining the side-effects of chemotherapeutic alkylating agents. |
| first_indexed | 2024-09-23T16:55:26Z |
| format | Article |
| id | mit-1721.1/108345 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:55:26Z |
| publishDate | 2017 |
| publisher | Impact Journals/National Center for Biotechnology Information (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/1083452022-09-29T22:27:03Z Parp1 protects against Aag-dependent alkylation-induced nephrotoxicity in a sex-dependent manner Bronson, Roderick T. Calvo, Jennifer Allocca, Mariacarmela Fake, Kimberly Muthupalani, Sureshkumar Corrigan, Joshua Samson, Leona D Massachusetts Institute of Technology. Center for Environmental Health Sciences Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Division of Comparative Medicine Calvo, Jennifer Allocca, Mariacarmela Fake, Kimberly Muthupalani, Sureshkumar Corrigan, Joshua Samson, Leona D ephrotoxicity is a common toxic side-effect of chemotherapeutic alkylating agents. Although the base excision repair (BER) pathway is essential in repairing DNA alkylation damage, under certain conditions the initiation of BER produces toxic repair intermediates that damage healthy tissues. We have shown that the alkyladenine DNA glycosylase, Aag (a.k.a. Mpg), an enzyme that initiates BER, mediates alkylation-induced whole-animal lethality and cytotoxicity in the pancreas, spleen, retina, and cerebellum, but not in the kidney. Cytotoxicity in both wild-type and Aag-transgenic mice (AagTg) was abrogated in the absence of Poly(ADP-ribose) polymerase-1 (Parp1). Here we report that Parp1-deficient mice expressing increased Aag (AagTg/Parp1-/-) develop sex-dependent kidney failure upon exposure to the alkylating agent, methyl methanesulfonate (MMS), and suffer increased whole-animal lethality compared to AagTg and wild-type mice. Macroscopic, histological, electron microscopic and immunohistochemical analyses revealed morphological kidney damage including dilated tubules, proteinaceous casts, vacuolation, collapse of the glomerular tuft, and deterioration of podocyte structure. Moreover, mice exhibited clinical signs of kidney disease indicating functional damage, including elevated blood nitrogen urea and creatinine, hypoproteinemia and proteinuria. Pharmacological Parp inhibition in AagTg mice also resulted in sensitivity to MMS-induced nephrotoxicity. These findings provide in vivo evidence that Parp1 modulates Aag-dependent MMS-induced nephrotoxicity in a sex-dependent manner and highlight the critical roles that Aag-initiated BER and Parp1 may play in determining the side-effects of chemotherapeutic alkylating agents. United States. National Institutes of Health (R01- CA075576) United States. National Institutes of Health (R01-CA055042) United States. National Institutes of Health (R01-CA149261) United States. National Institutes of Health (AGSS- 3046-12) United States. National Institutes of Health (P30-ES02109) United States. National Institutes of Health (P30-CA014051) 2017-04-21T17:02:53Z 2017-04-21T17:02:53Z 2016-07 2015-09 Article http://purl.org/eprint/type/JournalArticle 1949-2553 http://hdl.handle.net/1721.1/108345 Calvo, Jennifer A.; Allocca, Mariacarmela; Fake, Kimberly R.; Muthupalani, Sureshkumar; Corrigan, Joshua J.; Bronson, Roderick T. and Samson, Leona D. “Parp1 Protects Against Aag-Dependent Alkylation-Induced Nephrotoxicity in a Sex-Dependent Manner.” Oncotarget 7, no. 29(July 2016) © Impact Journals/National Center for Biotechnology Information (U.S.) https://orcid.org/0000-0002-7112-1454 en_US http://dx.doi.org/10.18632/oncotarget.10440 Oncotarget Creative Commons Attribution 3.0 Unported licence http://creativecommons.org/licenses/by/3.0/ application/pdf Impact Journals/National Center for Biotechnology Information (U.S.) Impact Journals |
| spellingShingle | Bronson, Roderick T. Calvo, Jennifer Allocca, Mariacarmela Fake, Kimberly Muthupalani, Sureshkumar Corrigan, Joshua Samson, Leona D Parp1 protects against Aag-dependent alkylation-induced nephrotoxicity in a sex-dependent manner |
| title | Parp1 protects against Aag-dependent alkylation-induced nephrotoxicity in a sex-dependent manner |
| title_full | Parp1 protects against Aag-dependent alkylation-induced nephrotoxicity in a sex-dependent manner |
| title_fullStr | Parp1 protects against Aag-dependent alkylation-induced nephrotoxicity in a sex-dependent manner |
| title_full_unstemmed | Parp1 protects against Aag-dependent alkylation-induced nephrotoxicity in a sex-dependent manner |
| title_short | Parp1 protects against Aag-dependent alkylation-induced nephrotoxicity in a sex-dependent manner |
| title_sort | parp1 protects against aag dependent alkylation induced nephrotoxicity in a sex dependent manner |
| url | http://hdl.handle.net/1721.1/108345 https://orcid.org/0000-0002-7112-1454 |
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