L-thyroxine modifies nephrotoxicity by regulating the apoptotic pathway: The possible role of CD38/ADP-ribosyl cyclase-mediated calcium mobilization - Fig 3

<p>(A-D) Kidneys of CIS (15mg/kg) administrated mouse showing (A) vacuolar degeneration (arrow) and necrosis of the renal tubular epithelial linings, hyaline droplets (dashed arrow) and hyaline cast (arrow head). (B) Many apoptotic cells and bodies (arrow) with presence of granular cast (dashed arrow) in the lumen of renal tubules. (C) Wide spread hyaline cast (H) in the lumen of the medullary tubules. (D) Glomerular congestion, hyperplasia of the podocytes and shrinkage of the glomerular tuft (arrow), notice the wide spread of hyaline droplets (upper left) in many tubules. (E-F) Kidney of IRR (6 Gy) mouse showing marked swelling, granular and vacuolar (upper left) degeneration of the renal tubular epithelial linings with many necrotic cells and granular cast (arrow) in the lumen of some tubules. (G) Kidney of CIS and L-TH pretreated mouse showing mild degeneration of the renal tubular epithelium with scattered necrotic cells and small granular cast in the lumen of few tubules (arrow). (H) Kidney of IRR and L-TH pretreated mouse showing good restoration of renal tissue with only mild tubular epithelial degenerative changes. (H&E, X400).</p

Effect of L-TH on serum uric acid (A), creatinine (B) and urea nitrogen (C) levels as well as biochemical analysis of oxidative status; H₂O₂ content (D) and catalase activity (E) in kidney tissues of all experimental groups.

<p>Acute renal injury was induced in male Swiss mice by single <i>i</i>.<i>p</i>. injection of cisplatin (15mg/kg) or gamma irradiation (6 Gy). Animals were pretreated with L-TH (1μg/kg) four hours before induction of nephrotoxicity. L-TH- and vehicle-treated mice were served as normal controls. Values are expressed as mean ± SEM (n = 6–8). ^<i>#</i><i>P</i>< 0.05: significantly different versus vehicle treated control; *<i>P</i>< 0.05, **<i>P</i>< 0.01: significantly different versus untreated control. CIS, cisplatin; H₂O₂, hydrogen peroxide; IRR, gamma irradiated; L-TH, L-thyroxine.</p

L-TH protects against CIS and IRR-induced apoptosis.

<p>Immunohistochemistry for caspase-3 and Bax showing positive expression among the renal tubular epithelium in both models of nephrotoxicity. Very mild to negative expressions of caspase-3 and Bax among the tubular epithelial linings in kidneys of pre-administered L-TH/cisplatin or L-TH/gamma irradiated mice (X 400).</p

Effect of L-TH on chemosensitivity of cisplatin.

<p>Caco-2 cells were pretreated with L-TH (30, 120 and 240 nM) or 5-AIQ (30 μM) four hours before incubation with cisplatin (60μM/24h). Cell viability was determined with MTT assay. 5-AIQ, 5-aminoisoquinoline; CIS, cisplatin; L-TH, L-thyroxine.</p

Effect of L-TH on serum uric acid (A), creatinine (B) and urea nitrogen (C) levels as well as biochemical analysis of oxidative status; H₂O₂ content (D) and catalase activity (E) in kidney tissues of all experimental groups.

<p>Acute renal injury was induced in male Swiss mice by single <i>i</i>.<i>p</i>. injection of cisplatin (15mg/kg) or gamma irradiation (6 Gy). Animals were pretreated with L-TH (1μg/kg) four hours before induction of nephrotoxicity. L-TH- and vehicle-treated mice were served as normal controls. Values are expressed as mean ± SEM (n = 6–8). ^<i>#</i><i>P</i>< 0.05: significantly different versus vehicle treated control; *<i>P</i>< 0.05, **<i>P</i>< 0.01: significantly different versus untreated control. CIS, cisplatin; H₂O₂, hydrogen peroxide; IRR, gamma irradiated; L-TH, L-thyroxine.</p

Pretreatment with L-TH antagonizes cisplatin-induced cellular death and modified the radiosensitivity.

<p><b>(A)</b> Vero cells were pretreated with L-TH (120 nM) for different exposure time before incubation with cisplatin (60μM/24h). L-TH protected the cells from cisplatin induced dose-dependent loss of viability and L-TH protected the cells from cisplatin-induced cell death in time-dependent effect. <b>(B)</b> The cells were pretreated with different doses of L-TH two hours before they were IRR with either 2 or 6 Gy dose levels. Cell viability was determined using MTT assay after 24h incubation. Data are expressed as mean (% of control) ± SEM of three independent experiments. (*) indicates significant difference versus CIS-treated or 2Gy-irradiated cells (*<i>P</i>< 0.05).</p