title: Parp1 protects against Aag-dependent alkylation-induced nephrotoxicity in a sex-dependent manner.
abstract: Nephrotoxicity 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.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.|Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Calvo
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.|Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Mariacarmela
authors.initials: M
authors.lastname: Allocca
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.|Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Fake
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Sureshkumar
authors.initials: S
authors.lastname: Muthupalani
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.|Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Corrigan
authors.affiliation: Rodent Histopathology Core, Harvard Medical School, Boston, MA, USA.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.|Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.|The David H. Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Leona D
authors.initials: LD
authors.lastname: Samson
mesh_terms: D000478:Alkylation; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects*; D004249:DNA Damage / Q000187:drug effects; D045647:DNA Glycosylases / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects; D005260:Female; D007668:Kidney / Q000187:drug effects*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism*; D012727:Sex Characteristics
chemical_list: D018906:Antineoplastic Agents, Alkylating; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; C021565:3-methyladenine-DNA glycosylase; D045647:DNA Glycosylases
keywords: Aag; MMS; Parp1; Pathology Section; alkylating agents; nephrotoxicity