Contrast media-induced nephropathy (CIN) is an acute deterioration of renal function following administration of contrast media (CM), due to combined hypoxic and toxic renal parenchymal injury, mediated, to large extent, by an increased production of reactive oxygen species (ROS) within the kidney Heyman SN, 1999 [1]. The different isoforms of superoxide dismutase (SOD) have recently attracted researchers’ attention for a possible protective role in CIN. We have recently isolated a novel isoform of a recombinant Manganese Superoxide Dismutase (rMnSOD), derived from a human established liposarcoma cell line (LSA), which shares the same ability of physiological SODs in transforming free radicals into hydrogen peroxide McCord JM, 1971 [2], but shows peculiar structural and functional properties. The rMnSOD, in fact, is linked to an uncleaved terminal peptide sequence (leading peptide) which, at difference with commercial SODs, allows the molecule to enter inside the cells after its administration Borrelli A, 2011 [3]. rMnSOD has been shown to be very effective in scavenging both intra- and extracellular O2-, hence improving pathological conditions associated with increased oxidative stress Borrelli A, 2009 [4]. Additionally, rMnSOD shows an excellent organ bioavalaibility and, therefore, seems well suited for correcting also renal oxidative stress.
Aim of this study was to evaluate whether rMnSOD could provide an effective protection against CIN.
We studied the effects rMnSOD on oxidative damage in a rat model of CIN: 27 uninephrectomized rats were randomly assigned to 3 experimental Groups: Group HCM (n=9), rats treated with CM; Group SOD (n=10), rats treated with CM and rMnSOD; Group CON (n=9), control rats treated with the vehicle of CM. We evaluated and compared glomerular filtration rate (GFR), rMnSOD presence and activity in the kidney, ROS production and renal histology in the rats of the 3 groups.
In comparison to rats pre-treated with vehicle, the rats of SOD group showed significantly reduced intrarenal O2- levels (-84%; p<0.0001) (Fig. 1) and a significant increase in SOD activity in kidneys (+16%; p=0.05) (Fig. 2). ROS production in rats of group HCM was almost doubled compared to rat of Group CON (12030 ± 300 vs 5286 ± 500 IF/gr of tissue/µg of proteins; p<0.01) (Fig. 3). Conversely, in rats of Group SOD ROS production overlapped those of Group CON (4579 ± 230 vs 5286 ± 500 IF/gr of tissue/µg of proteins) (Fig. 3). Glomerular filtration rate (GFR) averaged 0.92 ± 0.2 ml/min/100 g b.w. in control rats and was significantly depressed by 70% in rats of Group HCM (0.27 ± 0.1 ml/min/100 g b.w.; p<0.001 vs Group CON). Pre-treatment with rMnSOD determined a consistent preservation of renal function after the toxic insult, with GFR values significantly higher than those of Group HCM (0.66 ± 0.1 ml/min/100 g b.w., p < 0.05 vs HCM, but NS vs CON) (Fig. 3). All rats in group CM developed tubular necrosis, proteinaceous casts, and medullary congestion. Pre-treatment with rMnSOD attenuated the development of all these lesions, although significant protective effectswere observed only in tubular necrosis (P = 0.001) and proteinaceous cast (P < 0.001).
Our data indicate that rMnSOD is able to greatly reduce renal oxidative stress, and its associated reduction of GFR following CM administration. In addition, contrast-induced proteinuria, proteinaceous cast and tubular necrosis are restored by rMnSOD. These preliminary data suggest that the use of rMnSOD may open new perspectives in the treatment of CIN, as well as in many pathological conditions associated with increased oxidative stress.
[1] Heyman SN, Reichman J, Brezis M et al. Pathophysiology of radiocontrast nephropathy: a role for medullary hypoxia. Investigative radiology 1999 Nov;34(11):685-91
[2] McCord JM, Keele BB Jr, Fridovich I et al. An enzyme-based theory of obligate anaerobiosis: the physiological function of superoxide dismutase. Proceedings of the National Academy of Sciences of the United States of America 1971 May;68(5):1024-7
[3] Borrelli A, Schiattarella A, Mancini R et al. The leader peptide of a human rec. MnSOD as molecular carrier which delivers high amounts of Cisplatin into tumor cells inducing a fast apoptosis in vitro. International journal of cancer. Journal international du cancer 2011 Jan 15;128(2):453-9
[4] Borrelli A, Schiattarella A, Mancini R et al. A recombinant MnSOD is radioprotective for normal cells and radiosensitizing for tumor cells. Free radical biology & medicine 2009 Jan 1;46(1):110-6
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