Mechanisms of inhibited liver tissue repair in toxicant challenged type 2 diabetic rats |
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Authors: | Sawant Sharmilee P Dnyanmote Ankur V Mehendale Harihara M |
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Institution: | Department of Toxicology, College of Pharmacy, The University of Louisiana at Monroe, 700 University Avenue, Sugar Hall #306, Monroe, LA 71209-0470, USA. |
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Abstract: | Liver injury initiated by non-lethal doses of CCl(4) and thioacetamide (TA) progresses to hepatic failure and death of type 2 diabetic (DB) rats due to failed advance of liver cells from G(0)/G(1) to S-phase and inhibited tissue repair. Objective of the present study was to investigate cellular signaling mechanisms of failed cell division in DB rats upon hepatotoxicant challenge. In CCl(4)-treated non-diabetic (non-DB) rats, increased IL-6 levels, sustained activation of extracellular regulated kinases 1/2 (ERK1/2) MAPK, and sustained phosphorylation of retinoblastoma protein (p-pRB) via cyclin D1/cyclin-dependent kinase (cdk) 4 and cyclin D1/cdk6 complexes stimulated G(0)/G(1) to S-phase transition of liver cells. In contrast to the non-DB rats, CCl(4) administration led to lower plasma IL-6, decreased ERK1/2 activation, lower cyclin D1, and cdk 4/6 expression resulting in decreased p-pRB and inhibition of liver cell division in the DB rats. Furthermore, higher TGFbeta1 expression and p21 activation may also contribute to decreased p-pRB in DB rats compared to non-DB rats. Similarly, after TA administration to DB rats, down-regulation of cyclin D1 and p-pRB leads to markedly decreased advance of liver cells from G(0)/G(1) to S-phase and tissue repair compared to the non-DB rats. Hepatic ATP levels did not differ between the DB and non-DB rats obviating its role in failed tissue repair in the DB rats. In conclusion, decreased p-pRB may contribute to blocked advance of cells from G(0)/G(1) to S-phase and failed cell division in DB rats exposed to CCl(4) or TA, leading to progression of liver injury and hepatic failure. |
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Keywords: | CCl4 Liver injury Phospho-retinoblatoma Thioacetamide Tissue repair Type 2 diabetes |
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