Diabetes-induced oxidative DNA damage alters p53-p21CIP1/Waf1 signaling in the rat testis.
Diabetes is increasingly becoming a major cause of large-scale morbidity and mortality. Diabetes-induced oxidative stress alters numerous intracellular signaling pathways. Although testicular dysfunction is a major concern in diabetic men, the mechanistic alterations in the testes that lead to hypogonadism are not yet clear. Oxidative mitochondrial DNA damage, as indicated by 7,8-dihydro-8-oxo-2'-deoxyguanosine, and phosphorylation of p53 at ser315 residue (p-p53ser315) increased in a stage- and cell-specific manner in the testes of rats that were diabetic for 1 month (DM1). Prolongation of diabetes for 3 months (DM3) led to an increase in nuclear oxidative DNA damage in conjunction with a decrease in the expression of p-p53ser315. The nuclei of pachytene and preleptotene spermatocytes, steps 1, 11, and 12 spermatids, secondary spermatocytes and the Sertoli cells, and the meiotic figures showed an increase in the expression of p-p53ser315. An increase in the expression of a downstream target of p53 and protein 21(cyclin-dependent kinase interacting protein 1/wild-type p53-activated factor 1) (p21(CIP1/Waf1)) in both diabetic groups did not show any time-dependent effects but occurred concurrent with an upregulation of p-p53ser315 in DM1 and a downregulation of the protein in DM3. In diabetic groups, the expression of p21(CIP1/Waf1) was mainly cytoplasmic but also perinuclear in pachytene spermatocytes and round spermatids. The cytoplasmic localization of p21(CIP1/Waf1) may be suggestive of an antiapoptotic role for the protein. The perinuclear localization is probably related to the cell cycle arrest meant for DNA damage repair. Diabetes upregulates p21(CIP1/Waf1) signaling in testicular germ cells in association with alteration in p-p53ser315 expression, probably to counteract DNA damage-induced cell death.
Department of Anatomy, Faculty of Medicine, Health Science Center, Kuwait University, Kuwait knarayana@hsc.edu.kw.
Narayana
N
Kilarkaje
Department of Physiology, Faculty of Medicine, Health Science Center, Kuwait University, Kuwait.
Maie M
MM
Al-Bader
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018384:Oxidative Stress; D010766:Phosphorylation; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013094:Spermatozoa / Q000378:metabolism* / Q000473:pathology; D013737:Testis / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004272:DNA, Mitochondrial; D016159:Tumor Suppressor Protein p53; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine
DNA damage repair; cell cycle control; diabetes; germ cell apoptosis; testicular dysfunction