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.
Highlights
The kidney is essential for excretion of waste and maintenance of proper osmotic and oncotic pressure; these functions require a properly functioning filtration unit comprised of the glomerulus and surrounding Bowman’s capsule
Alkylation-induced damage in numerous tissues is suppressed in Aag-transgenic mice (AagTg)/Poly(ADP-ribose) polymerase-1 (Parp1)-/- mice [12], whole-animal toxicity is not suppressed; rather, the animals are more susceptible to methyl methanesulfonate (MMS)-induced whole-animal lethality
Protected from MMS-induced toxicity in a variety of tissues, AagTg/Parp1-/- mice eventually succumb to whole-animal lethality at lower MMS doses in comparison to AagTg mice
Summary
The kidney is essential for excretion of waste and maintenance of proper osmotic and oncotic pressure; these functions require a properly functioning filtration unit comprised of the glomerulus and surrounding Bowman’s capsule. Blood is filtered within the filtration unit; protein, cells, and specific concentrations of chemicals are retained, whereas waste and extra fluid is passed to the renal tubules to become urine. One common feature of glomerular dysfunction is loss of protein from the blood (hypoproteinemia) accompanied by increased urinary protein (proteinuria). Glomerular dysfunction can cause chronic kidney disease and eventually endstage renal disease (ESRD), requiring dialysis or kidney transplantation. Various causes include genetic mutations, www.impactjournals.com/oncotarget autoimmunity, infections, environmental exposures or any combination thereof (reviewed in [1-4]). Pathological changes damaging the glomerular filtration apparatus are responsible for 90% of ESRD, resulting in ~$20 billion in yearly health costs in the USA [5]
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