5-aminoisoquinoline improves renal function and fibrosis during recovery phase of cisplatin-induced acute kidney injury in rats.

Andrés Quesada,Sebastián Montoro-Molina,Rosemary Wangensteen,Juan Francisco González,Mercedes Gómez-Morales,Mercedes Caba-Molina,Francisco O’Valle,Antonio Osuna,Félix Vargas,María C De Gracia

doi:10.1042/bsr20171313

Abstract

The aim of the present study is to analyze the effects of 5-aminoisoquinoline (5-AIQ), a poly(ADP-ribose) polymerase-1 (PARP1) inhibitor, over renal dysfunction and fibrosis during recovery phase of cisplatin (CisPt)-induced acute kidney injury (AKI) in rats. Male Wistar rats were distributed in three groups (n=8 each group): control, CisPt, and CisPt + 5-AIQ. Control and CisPt groups received a subcutaneous injection of either saline or 7 mg/kg CisPt, respectively. CisPt + 5-AIQ group received two intraperitoneal injections of 10 mg/kg 5-AIQ 2 h before and 24 h after CisPt treatment. Thirteen days after the treatment, rats were housed in metabolic cages and 24-h urine collection was made. At day 14, CisPt-treated rats showed increased diuresis, N-acetyl-β-d-glucosaminidase (NAG) excretion, glucosuria and sodium fractional excretion (NaFE), and decreased creatinine clearance (CrCl). 5-AIQ significantly increased CrCl and decreased NAG excretion, glucosuria, and NaFE. In plasma, CisPt increased sodium, urea, and creatinine concentrations, while 5-AIQ treatment decreased these variables to the levels of control group. 5-AIQ completely prevented the body weight loss evoked by CisPt treatment. CisPt also induced an increased renal expression of PAR polymer, α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and collagen-IV. These variables were decreased in CisPt + 5-AIQ group. Tubular lesions and renal fibrosis were also decreased by 5-AIQ treatment. We conclude that inhibition of PARP1 with 5-AIQ can attenuate long-term nephrotoxic effects associated with the CisPt treatment, preventing renal dysfunction and body weight decrease and ameliorating tubular lesions and collagen deposition.

Highlights

Cisplatin (CisPt) is an antitumoral agent that induces direct proximal tubular nephrotoxicity in both humans and animals [1,2]
Inhibition of poly(ADP-ribose) polymerase 1 (PARP1) with 5-AIQ evoked an increase in creatinine clearance (CrCl) in CisPt-treated rats and no significant differences were found between CisPt + 5-AIQ and c 2018 The Author(s)
The main findings of this work are that inhibition of PARP1 with 5-AIQ ameliorates renal dysfunction and prevents body weight loss, decreasing renal fibrosis and tubular lesions in CisPt treated rats 2 weeks after the treatment

Summary

Introduction

Cisplatin (CisPt) is an antitumoral agent that induces direct proximal tubular nephrotoxicity in both humans and animals [1,2]. This side effect limits the use of CisPt because one-third of the patients develop renal dysfunction after CisPt treatment [3,4,5]. The mechanisms implicated in CisPt nephrotoxicity are not completely elucidated, it has been published that poly(ADP-ribose) polymerase 1 (PARP1) is an important mediator of CisPt-induced renal tubular necrosis and inflammation [6,7]. PARP1 is a nuclear enzyme that repairs DNA strands in homeostatic conditions, converting NAD+ into ADP-ribose. Its overactivation in several pathological conditions induces a depletion of NAD+ and ATP that triggers cellular death and up-regulation of key inflammatory pathways [8,9].

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