Organ function, sphingolipid levels and inflammation in tunicamycin induced endoplasmic reticulum stress in male rats

AYDIN ASLAN M., Elpek O., AKKAYA B., TUZCU BALABAN H., Afsar E.

HUMAN & EXPERIMENTAL TOXICOLOGY, cilt.40, sa.2, ss.259-273, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 40 Sayı: 2
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1177/0960327120949619
  • Dergi Adı: HUMAN & EXPERIMENTAL TOXICOLOGY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, PASCAL, BIOSIS, CAB Abstracts, Chimica, CINAHL, EMBASE, Environment Index, Food Science & Technology Abstracts, MEDLINE, Pollution Abstracts, Veterinary Science Database
  • Sayfa Sayıları: ss.259-273
  • Anahtar Kelimeler: Endoplasmic reticulum stress, ceramide, cytosolic phospholipase A2, cyclooxygenase-2, INDUCED CELL-DEATH, ER STRESS, CERAMIDE, APOPTOSIS, LIVER, ERYTHROPOIETIN, HEPATOCYTES, INHIBITION, METABOLISM, INDUCTION
  • Akdeniz Üniversitesi Adresli: Evet

Özet

Disorders of the endoplasmic reticulum (ER) lead to cellular damage but can cause cell death if ER dysfunction is prolonged. We aimed to examine liver/kidney functions, neutral sphingomyelinase (N-SMase) activity, sphingolipid levels, cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX-2) protein expression in rats under ER stress. ER stress was induced by tunicamycin (TM) and the ER stress inhibitor taurodeoxycholic acid (TUDCA) was injected before induction of ER stress. ER stress was confirmed by increased tissue levels of GRP78. Hematological and biochemical profiles were measured by autoanalyzers while hepatic and renal injury was evaluated via microscopy and histopathological scoring. Tissue levels of C16-C24 sphingomyelins (SM), C16-C24 ceramides (CERs) and sphingosine-1-phosphate (S1P) were determined by LC-MS/MS. Tissue cPLA2 and COX-2 were measured by western blot and activity assays. Tunicamycin treatment caused kidney and liver function test abnormalities, increased hematocrit and hemoglobin levels but decreased white blood cell counts. Histopathological findings showed hepatic necroinflammation and renal tubular damage in rats treated with TM. TUDCA administration attenuated WBC abnormalities and TM- induced hepatic/renal functional impairment in ER stress, as evident by significantly restored serum ALT, AST, creatinine, and total bilirubin levels. A significant increase was observed in N-SMase activity, tissue levels of C16-C24 CERs, cPLA2 and COX-2 expression in liver and kidney tissue under ER stress. TUDCA administration decreased tissue CER levels, cPLA2 and COX-2 expression as well as prostaglandin E2 (PGE2) formation. These results signify that ER stress causes hepatic and renal toxicity as well as CER-induced PGE2 formation in liver and kidney.