L-thyroxine modifies nephrotoxicity by regulating the apoptotic pathway: The possible role of CD38/ADP-ribosyl cyclase-mediated calcium mobilization

Abstract

Thyroid hormones are well-established as a key regulator of many cellular metabolic pathways developed in various pathogeneses. Here, we dedicated the current work to investigate the role of thyroid hormone analogue (L-thyroxine, L-TH) in regulating the renal cytotoxicity using in vivo and in vitro models. Swiss mice were exposed to gamma radiation (IRR, 6Gy) or treated with cisplatin (CIS, 15 mg/kg, i.p.) for induction of nephrotoxicity. Remarkably, pretreatment with L-TH (1μg/kg) ameliorated the elevated kidney function biomarkers, oxidative stress and protected the renal tissue from the subsequent cellular damage. Likewise, L-TH inhibited the apoptotic cascade by down-regulating the extreme consumption of the cellular energy (ATP), the expression of caspase-3 and Bax, and the stimulation of cyclic ADP ribose (cADPR)/calcium mobilization. Moreover, incubation with L-TH (120nM/4h) significantly blocked the cytotoxicity of CIS on Vero cells and the depletion of NAD+ content as well as modified the ADP-ribose cyclase (CD38) enzymatic activity. High doses of L-TH (up to30 nM/4h) inversely increased the radiosensitivity of Vero cells towards IRR (up to 6Gy). On the other hand, L-TH did not interfere CIS-induced cytotoxicity of colorectal adenocarcinoma (Caco-2) cell line. In conclusion, pretreatment with L-TH could be a promising protective approach to the renal cellular damage induced during either CIS or IRR therapy by regulating the unbalanced oxidative status, the expression of pro-apoptotic biomarkers via modulation of cADPR mediated-calcium mobilization.

Cisplatin-Induced Kidney Toxicity: Potential Roles of Major NAD+-Dependent Enzymes and Plant-Derived Natural Products

“…Nevertheless, a limited number of studies have shed light on these NAD + -dependent redox enzymes. For example, it has been reported that CD38 can mediate calcium mobilization in cisplatin-induced kidney injury [ 87 ]. Likewise, poly-ADP ribosylase has been found to be activated in cisplatin-induced kidney injury [ 88 ] and enhancement of sirtuin protein function can attenuate cisplatin-induced kidney injury [ 89 ].…”

Polyphenols, Luteolin and Pelargonidin, Modulate Radio- and Chemo-Sensitivity on Breast Cancer

“…The irradiation of process was carried out at the National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Nasr City, Cairo, Egypt, using the Gamma cell®-40 biological irradiator with Caesium137 source (Atomic Energy of Canada Limited; Sheridan Science and Technology Park, Mississauga, Ontario, Canada) at a 0.643 Gy/min dose rate. To elucidate the possible glycogen synthase kinase-3β (GSK-3β)-dependent mechanism, cells were pretreated with GSK-3β inhibitor (AR-A 014418, 1 µM) before being treated with LUT (El-Hamoly et al, 2017).…”

Radioiodination of 5-aminoisoquinoline for Poly (ADP-ribose) Polymerase Targeting: An In vitro Evaluation in Colorectal Carcinoma Cells

“…They were passaged at 80-90% confluency after trypsinization with pre-warmed trypsin-EDTA solution. Cells were incubated (4h, at different concentrations) with either the PARP inhibitor (5-AIQ) or its iodinated analogue before evaluation of cytotoxicity (El-Hamoly et al, 2017).…”

“…Confluent cells (10 5 cells/mL) were inoculated in 96-well plate with either 5-AIQ or its iodinated product (R) four hours at 37 o C. At the end of the experiment, 20 µl of 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) solution was added to each well and then incubated for one extra hour. The absorbance of living cells was measured at 560 nm (El-Hamoly et al, 2017).…”