Restored nitric oxide bioavailability reduces the severity of acute-to-chronic transition in a mouse model of aristolochic acid nephropathy

Abstract

Aristolochic Acid (AA) nephropathy (AAN) is a progressive tubulointerstitial nephritis characterized by an early phase of acute kidney injury (AKI) leading to chronic kidney disease (CKD). The reduced nitric oxide (NO) bioavailability reported in AAN might contribute to renal function impairment and progression of the disease. We previously demonstrated that L-arginine (L-Arg) supplementation is protective in AA-induced AKI. Since the severity of AKI may be considered a strong predictor of progression to CKD, the present study aims to assess the potential benefit of L-Arg supplementation during the transition from the acute phase to the chronic phase of AAN. C57BL/6J male mice were randomly subjected to daily i.p. injections of vehicle or AA for 4 days. To determine whether renal AA-induced injuries were linked to reduced NO production, L-Arg was added to drinking water from 7 days before starting i.p. injections, until the end of the protocol. Mice were euthanized 5, 10 and 20 days after vehicle or AA administration. AA-treated mice displayed marked renal injury and reduced NO bioavailability, while histopathological features of AAN were reproduced, including interstitial cell infiltration and tubulointerstitial fibrosis. L-Arg treatment restored renal NO bioavailability and reduced the severity of AA-induced injury, inflammation and fibrosis. We concluded that reduced renal NO bioavailability contributes to the processes underlying AAN. Furthermore, L-Arg shows nephroprotective effects by decreasing the severity of acute-to-chronic transition in experimental AAN and might represent a potential therapeutic tool in the future.

Aristolochic Acid-Induced Nephrotoxicity: Molecular Mechanisms and Potential Protective Approaches

“…In addition, AA-treated zebrafish embryos showed a blood cell accumulation in the kidney that triggered inflammation, which was evidenced by upregulation of the expression of proinflammatory genes, including tumor necrosis factor alpha (TNFα), cyclooxygenase (COX-2), myeloperoxidase (MPO), and interleukin 1 beta (IL-1β) [72]. Similarly, Jadot and colleagues observed an increase in renal mRNA expression of proinflammatory cytokines, including IL-6, IL-1β, and TNFα, following the treatment of mice with AA [73]. Recently, NLRP3 inflammasome, a multimeric protein complex that initiates an inflammatory form of cell death, has been reported to be implicated in AA-mediated nephrotoxicity.…”

“…Nitric oxide (NO) is involved in the regulation of renal blood flow. Studies have reported that AAN is associated with decreased NO bioavailability [73]. In this regard, Declèves and colleagues showed that administration of L-arginine, a precursor of NO, restored its bioavailability and ameliorated AKI in mice treated with AA [50].…”

“…In this regard, Declèves and colleagues showed that administration of L-arginine, a precursor of NO, restored its bioavailability and ameliorated AKI in mice treated with AA [50]. Additionally, it was reported that L-arginine supplementation also delayed the progression of AKI to CKD in C57BL/6J mice treated with AA [73].…”

A Translational Metabonomic Assessment of Aristolochic Acid- Induced Nephropathies

“…C57Bl/6 J male mice were daily i.p. injected with a solution of AAI (3.5 mg/kg) for 4 days and then sacrificed at 5, 10 or 20 days after the first day of injection [15,39]. The acute phase was identified at day 5 with necrosis of PTEC while at day 20, cystic tubules and tubulointerstitial fibrosis was observed characterizing the features of a chronic phase.…”

Subcellular trafficking of tubular MDM2 implicates in acute kidney injury to chronic kidney disease transition during multiple low‐dose cisplatin exposure

“…[15][16][17][18] More importantly, CP is widely used in clinic due to its high efficiency, and to avoid its nephrotoxicity clinicians usually adopt a multiple low-dose administration. [15][16][17][18] More importantly, CP is widely used in clinic due to its high efficiency, and to avoid its nephrotoxicity clinicians usually adopt a multiple low-dose administration.…”