Protective effect of calcitriol on rhabdomyolysis-induced acute kidney injury in rats

Reis, Natany Garcia; Francescato, Heloı́sa Della Coletta; Almeida, Lucas Ferreira de; Silva, Cleonice Giovanini Alves da; Costa, R. S.; Coimbra, Terezila Machado

doi:10.1038/s41598-019-43564-1

Cited by 26 publications

(24 citation statements)

References 32 publications

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“…, 90 Paricalcitol, a novel synthetic vitamin D analogue mitigated contrast-induced nephropathy by inhibiting renal and systemic oxidative stress. Vitamin D, by virtue of its antioxidant effects, offers protection against aminoglycoside-induced nephrotoxicity, 91,92 cyclosporine-mediated kidney injury, 93 rhabdomyolysis-induced AKI, 94 and lipopolysaccharide-induced AKI. 95 Additionally, vitamin D deficiency seemed to aggravate renal inflammation, cell proliferation, and cell injury in experimental ischemia-reperfusion injury, indicating the need for sufficient vitamin D levels.…”

Section: Discussionmentioning

confidence: 99%

Ferrotoxicity and its amelioration by endogenous vitamin D in experimental acute kidney injury

Annamalai

Ganesh

Viswanathan

2020

Exp Biol Med (Maywood)

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Acute kidney injury causes significant morbidity and mortality. This experimental animal study investigated the simultaneous impact of iron and vitamin D on acute kidney injury induced by iohexol, an iodinated, non-ionic monomeric radiocontrast agent in Wistar rats. Out of 36 healthy male Wistar rats, saline was injected into six control rats (group 1) and iohexol into the remaining 30 experimental rats (groups 2 to 6 comprising six rats each). Biochemical, renal histological changes, and gene expression of iron-regulating proteins and 1 α-hydroxylase were analyzed. Urinary neutrophil gelatinase-associated lipocalin (NGAL), serum creatinine, urine protein, serum and urine catalytic iron, 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3, and tissue lipid peroxidation were assayed. Rats injected with iohexol showed elevated urinary NGAL (11.94 ± 6.79 ng/mL), serum creatinine (2.92 ± 0.91 mg/dL), and urinary protein levels (11.03 ± 9.68 mg/mg creatinine) together with histological evidence of tubular injury and iron accumulation. Gene expression of iron-regulating proteins and 1 α-hydroxylase was altered. Serum and urine catalytic iron levels were elevated (0.57 ± 0.17; 48.95 ± 29.13 µmol/L) compared to controls (0.49 ± 0.04; 20.7 ± 2.62 µmol/L, P < 0.001). Urine catalytic iron positively correlated with tissue peroxidation (r = 0.469, CI 0.122 to 0.667, P = 0.004) and urinary NGAL (r = 0.788, CI 0.620 to 0.887, P < 0.001). 25-hydroxyvitamin D3 (61.58 ± 9.60 ng/mL) and 1,25-dihydroxyvitamin D3 (50.44 ± 19.76 pg/mL) levels increased simultaneously. In a multivariate linear regression analysis, serum iron, urine catalytic iron, and tissue lipid peroxidation independently and positively predicted urinary NGAL, an acute kidney injury biomarker. This study highlights the nephrotoxic potential of catalytic iron besides demonstrating a concurrent induction of vitamin D endogenously for possible renoprotection in acute kidney injury. Impact statement This work provides in-depth insights on catalytic iron-induced cytotoxicity and the resultant triggering of endogenous vitamin D synthesis in experimental acute kidney injury. Our results reveal significantly elevated levels of catalytic iron culminating in oxidant-mediated renal injury and a concomitant increase in 1,25-dihdyroxyvitamin D3 levels. Also, changes in other iron-related proteins including transferrin, ferritin, and hepcidin were observed both in the serum as well as in their mRNA expression. We consider all these findings vital since no connection between catalytic iron and vitamin D has been established so far. Furthermore, we believe that this work provides new and interesting results, with catalytic iron emerging as an important target in ameliorating renal cellular injury, possibly by timely administration of vitamin D. It also needs to be seen if these observations made in rats could be translated to humans by means of robust clinical trials.

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Section: Discussionmentioning

confidence: 99%

Ferrotoxicity and its amelioration by endogenous vitamin D in experimental acute kidney injury

Annamalai

Ganesh

Viswanathan

2020

Exp Biol Med (Maywood)

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“…Most studies based on glycerol damage applied quantities of 50-100 µl of glycerol per mouse TA muscle (Lluís et al, 2001;Mahdy et al, 2015;Mahdy, 2018). This protocol was also used to induce massive rhabdomyolysis, in particular for the investigation of acute kidney disease (Korrapati et al, 2012;Huang et al, 2018;Reis et al, 2019). However, since we were more interested in the effects of ASCs on muscle and NMJ regeneration, a milder protocol was sought.…”

Section: Low-dose Application Of Glycerol To Study Skeletal Muscle Dementioning

confidence: 99%

Effects of ASC Application on Endplate Regeneration Upon Glycerol-Induced Muscle Damage

Rigon

Hörner

Straka

et al. 2020

Front. Mol. Neurosci.

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Amongst other approaches, adipose-derived stromal cells (ASCs) have recently been tested with respect to their regenerative capacity for treatment of neuromuscular disorders. While beneficial effects of ASCs on muscle recovery were observed previously, their impact on regeneration of neuromuscular junctions (NMJs) is unclear. Here, we used a murine glycerol damage model to study disruption and regeneration of NMJs and to evaluate the effects of systemic application of ASCs on muscle and NMJ recovery. In mice that were not treated with ASCs, a differential response of NMJ preand post-synapses to glycerol-induced damage was observed. While post-synapses were still present in regions that were necrotic and lacking actin and dystrophin, presynapses disappeared soon in those affected areas. Partial regeneration of NMJs occurred within 11 days after damage. ASC treatment slightly enhanced NMJ recovery and reduced the loss of presynaptic sites, but also led to a late phase of muscle necrosis and fibrosis. In summary, the results suggest a differential sensitivity of NMJ pre-and post-synapses to glycerol-induced muscle damage and that the use of ASC for the treatment of neuromuscular disorders needs further careful evaluation.

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“…Paricalcitol, the synthetic vitamin D analogue, was elucidated by Ari et al [ 100 ] to circumvent contrast-induced nephropathy by reducing oxidative stress. By virtue of its antioxidant effects, vitamin D was found to protect against AKI induced by aminoglycoside [ 102 , 104 ], cyclosporine [ 105 ], rhabdomyolysis [ 106 ], and lipopolysaccharide [ 107 ]. Moreover, deficient calcitriol levels appeared to exacerbate inflammatory responses in rats with ischemia reperfusion injury [ 108 ].…”

Section: Discussionmentioning

confidence: 99%

Ferrotoxicity and Its Amelioration by Calcitriol in Cultured Renal Cells

Annamalai

Seth

Viswanathan

2021

Analytical Cellular Pathology

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Globally, acute kidney injury (AKI) is associated with significant mortality and an enormous economic burden. Whereas iron is essential for metabolically active renal cells, it has the potential to cause renal cytotoxicity by promoting Fenton chemistry-based oxidative stress involving lipid peroxidation. In addition, 1,25-dihydroxyvitamin D3 (calcitriol), the active form of vitamin D, is reported to have an antioxidative role. In this study, we intended to demonstrate the impact of vitamin D on iron-mediated oxidant stress and cytotoxicity of Vero cells exposed to iohexol, a low osmolar iodine-containing contrast media in vitro. Cultured Vero cells were pretreated with 1,25-dihydroxyvitamin D3 dissolved in absolute ethanol (0.05%, 2.0 mM) at a dose of 1 mM for 6 hours. Subsequently, iohexol was added at a concentration of 100 mg iodine per mL and incubated for 3 hours. Total cellular iron content was analysed by a flame atomic absorption spectrophotometer at 372 nm. Lipid peroxidation was determined by TBARS (thiobarbituric acid reactive species) assay. Antioxidants including total thiol content were assessed by Ellman’s method, catalase by colorimetric method, and superoxide dismutase (SOD) by nitroblue tetrazolium assay. The cells were stained with DAPI (4 ′ ,6-diamidino-2-phenylindole), and the cytotoxicity was evaluated by viability assay (MTT assay). The results indicated that iohexol exposure caused a significant increase of the total iron content in Vero cells. A concomitant increase of lipid peroxidation and decrease of total thiol protein levels, catalase, and superoxide dismutase activity were observed along with decreased cell viability in comparison with the controls. Furthermore, these changes were significantly reversed when the cells were pretreated with vitamin D prior to incubation with iohexol. Our findings of this in vitro model of iohexol-induced renotoxicity lend further support to the nephrotoxic potential of iron and underpin the possible clinical utility of vitamin D for the treatment and prevention of AKI.

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Protective effect of calcitriol on rhabdomyolysis-induced acute kidney injury in rats

Cited by 26 publications

References 32 publications

Ferrotoxicity and its amelioration by endogenous vitamin D in experimental acute kidney injury

Ferrotoxicity and its amelioration by endogenous vitamin D in experimental acute kidney injury

Effects of ASC Application on Endplate Regeneration Upon Glycerol-Induced Muscle Damage

Ferrotoxicity and Its Amelioration by Calcitriol in Cultured Renal Cells

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