Resveratrol Restores Type 2 Diabetes‐induced Alterations in Transcriptional Regulation of DNA Damage Repair Pathway genes in Goto‐Kakizaki Rats
Authors: Kilarkaje Narayana , Alqaryyan Mariam , Al‐Hussaini Heba , Al‐Bader Maie 
Published: June 2021

Background

Type 2 diabetes (T2DM)‐ characterized by insulin resistance and hyperglycemia‐affects organ systems resulting in macrovascular and microvascular complications. T2DM also induces DNA damage in varieties of cells, including germ cells, which forms a basis for the increased incidence of cancers in diabetic patients. The present study investigated modulatory effects of Resveratrol on gene expressions of DNA damage repair pathway‐related proteins in non‐obese Goto‐Kakizaki (GK) T2DM rats.

Methods

Two groups of adult male GK rats (70‐day‐old), a T2DM group and a T2DM+R (DMR) group, along with an age‐ and sex‐matched Wistar rat control group were used. Resveratrol (20 mg/kg; po) was given once daily for 120 days. Body weight and blood glucose levels were measured once a week. The animals were killed on day 121 and testes were removed and processed for RNA extraction. The quantitative analysis of 84 DNA damage repair pathway genes was carried out using SABiosciences RT2 Profiler™ PCR Array. The gene expression (2−ΔΔct) was considered regulated when the expression showed a minimum of 2‐fold increase/decrease compared to that in controls, and the Student's t‐test detected statistical significance at P<0.05 level.

Results

Of the 84 genes studied, only 25 (30%) genes were differentially regulated either in DM or DMR groups. Diabetes increased the expression of apoptosis‐related genes‐ Mbd4 (methyl‐CpG‐binding domain), Mgmt (O6‐methylguanine‐DNA methyltransferase) which Resveratrol recovered to control levels in DMR group (P<0.05). Diabetes also increased the expression of cell cycle control genes‐ Hus1 (checkpoint protein) and Cdc25c (cell division cycle 25c) and decreased that of Cdkn1a (cyclin‐dependent kinase inhibitor 1a). Resveratrol treatment recovered the expression of only Cdc25c in DMR group. Diabetes increased the expression of base‐excision repair (BER) related genes‐ Apex1 (DNA lyase), Mpg (DNA‐methyladenine glycosylase), Parp1 ((poly(ADP‐ribose) polymerase)), and Parp2, and nucleotide excison repair (NER) genes‐Dclre1a (DNA cross‐link repair protein), Rnf (Ubiquitinase), Xpc (xeroderma pigmentation complementation), and double‐strand breaks repair (DSBR) genes‐ Prkdc (DNA‐dependent protein kinase), Rad51c (DNA repair protein), Rad52, Blm (Bloom syndrome), and Rpa1 (Replication protein), and other genes related to DNA damage repair‐ Wrn (Helicase), Poli (DNA polymerase iota), and Sirt1 (Sirtuin) (P<0.05). Resveratrol recovered the expression of the genes mentioned earlier in DMR group, except that of Dclre1a, Rad52, Blm, Wrn, and Poli. In consensus with the gene expressions, diabetes increased DNA damage in testicular cells, and Resveratrol recovered the damage to the control level in DMR group.

Conclusions

Resveratrol decreases DNA damage due to which diabetes‐induced pro‐apoptotic and pro‐cell cycle arrest gene expressions recovered to control level. The increased DNA damage upregulates gene expressions related to BER, NER, and DSBR. Resveratrol‐mediated prevention/alleviation of DNA damage results in normalization of expressions of DNA damage repair pathway genes. (Supported by Kuwait University Grant#RM01/12 and SRUL02/13).

Support or Funding Information

Supported by Kuwait University Grant#RM01/12 and SRUL02/13

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.