Protective effect of nitric oxide in aristolochic acid-induced toxic acute kidney injury:an old friend with new assets

New Findings: What is the central question of this study? Despite the fact that the pathogenesis of aristolochic acid (AA) nephropathy is still unclear, we sought to determine whether nitric oxide is involved in the underlying mechanism of AA-induced acute kidney injury (AKI). What is the main finding and its importance? Using a model of progressive tubulointerstitial nephritis, in which AA nephropathy exhibits two interconnected phases, an acute phase and a chronic phase of injury, we demonstrated that maintenance of nitric oxide bioavailability is essential to improve the outcome of AA-induced AKI. Aristolochic acid (AA) nephropathy (AAN), a progressive tubulointerstitial injury of toxic origin, is characterized by early and transient acute tubular necrosis. This process has been demonstrated to be associated with reduced nitric oxide (NO) production, which can disrupt the regulation of renal function. In this study, we tested the hypothesis that l-arginine (l-Arg) supplementation could restore renal function and reduce renal injury after AA intoxication. C57BL/6 J male mice were randomly subjected to daily i.p. injection of either sterile saline solution or AA (2.5 mg kg−1) for 4 days. To determine whether AA-induced renal injuries were linked to reduced NO production, l-Arg, a substrate for NO synthase, was supplemented (5%) in drinking water. Mice intoxicated with AA exhibited features of rapid-onset acute kidney injury, including polyuria, significantly increased plasma creatinine concentrations, proteinuria and fractional excretion of sodium (P < 0.05), along with severe proximal tubular cell injury and increased NADPH oxidase 2 (Nox2)-derived oxidative stress (P < 0.05). This was associated with a significant reduction in NO bioavailability. l-Arg supplementation in AA-treated mice significantly increased NO bioavailability, which in turn improved renal function (creatininaemia, polyuria, proteinuria, fractional excreted sodium and N-acetyl-β-d-glucosaminidase enzymuria) and renal structure (tubular necrosis and tubular cell apoptosis). These changes were associated with significant reductions in Nox2 expression and in production of reactive oxygen species and with an increase in antioxidant concentrations. Our results demonstrate that preservation of NO bioavailability leads to renal protection in AA-induced acute kidney injury by reducing oxidative stress and maintaining renal function.SCOPUS: ar.jFLWINinfo:eu-repo/semantics/publishe

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

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.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Hyaluronidase 1 and hyaluronidase 2 are required for renal hyaluronan turnover

Hyaluronidase 1 (HYAL1) and hyaluronidase 2 (HYAL2) are the major hyaluronidases acting synergistically to degrade hyaluronan (HA). In the kidney, HA is distributed heterogeneously. Our goal was to determine the consequences of a lack of either HYAL1 or HYAL2 (using specific knockout mice) on renal function and on renal HA accumulation. Experiments were performed in Hyal1-/- and Hyal2-/- mice and in their wild-type controls. HA concentration was measured in the plasma and kidney tissue and its distribution through the different kidney zones was examined by immunohistochemistry. Relative mRNA expressions of HYAL1, HYAL2 and the 3 main HA synthases were evaluated by quantitative RT-PCR. Results: Kidney function was not impaired in the knockout mice but they displayed elevated HA concentrations in the plasma and in the kidney. Hyal1-/- mice presented an accumulation of HA inside the proximal tubular cells whereas Hyal2-/- mice showed HA accumulation in the interstitial space. In the cortex and in the outer medulla, HYAL1 mRNA expression was up-regulated in Hyal2-/- mice. From our study we conclude that somatic hyaluronidases are not required for renal function. However, HYAL1 is necessary for the breakdown of intracellular HA in the cortex, whereas HYAL2 is essential for the degradation of extracellular HA in all kidney regions.SCOPUS: ar.jSCOPUS: ar.jinfo:eu-repo/semantics/publishe