The antioxidant and DNA-repair enzyme apurinic/apyrimidinic endonuclease 1 limits the development of tubulointerstitial fibrosis partly by modulating the immune system

• Published in: Scientific reports Vol. 9; no. 1; p. 7823
• Main Authors: Maruyama, Keisuke, Nakagawa, Naoki, Aonuma, Tatsuya, Saito, Yukihiro, Hayasaka, Taiki, Kano, Kohei, Horiuchi, Kiwamu, Takehara, Naofumi, Kawabe, Jun-ichi, Hasebe, Naoyuki
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.05.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/44; 13/51; 38/90; 38/91; 631/114; 692/4022/1585; Animals; Antioxidants; Apoptosis; Chemokines; Computational Biology; Deoxyribonucleic acid; Disease Models, Animal; DNA; DNA repair; DNA Repair - immunology; DNA-(Apurinic or Apyrimidinic Site) Lyase - genetics; DNA-(Apurinic or Apyrimidinic Site) Lyase - therapeutic use; Endonuclease; Fibrosis; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Humanities and Social Sciences; Humans; Immune system; Immunity - genetics; Injection; Injections, Intravenous; Interleukin 6; Kidney Tubules - immunology; Kidney Tubules - pathology; Kidneys; Male; Mice; multidisciplinary; Nephritis, Interstitial - genetics; Nephritis, Interstitial - immunology; Nephritis, Interstitial - pathology; Nephritis, Interstitial - therapy; Oxidative stress; Oxidative Stress - genetics; Oxidative Stress - immunology; Plasmids - administration & dosage; Plasmids - genetics; Renal Veins; Ribonucleic acid; RNA; RNA-Seq; Science; Science (multidisciplinary); Transcription; Tumor necrosis factor
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-44241-z

Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional protein that controls the cellular response to oxidative stress and possesses DNA-repair functions. It has important roles in the progression and outcomes of various diseases; however, its function and therapeutic prospects with respect to kidney injury are unknown. To study this, we activated APE1 during kidney injury by constructing an expression vector (pCAG-APE1), using an EGFP expression plasmid (pCAG-EGFP) as a control. We performed unilateral ureteral obstruction (UUO) as a model of tubulointerstitial fibrosis on ICR mice before each vector was administrated via retrograde renal vein injection. In this model, pCAG-APE1 injection did not produce any adverse effects and significantly reduced histological end points including fibrosis, inflammation, tubular injury, and oxidative stress, as compared to those parameters after pCAG-EGFP injection. qPCR analysis showed significantly lower expression of Casp3 and inflammation-related genes in pCAG-APE1-injected animals compared to those in pCAG-EGFP-injected UUO kidneys. RNA-Seq analyses showed that the major transcriptional changes in pCAG-APE1-injected UUO kidneys were related to immune system processes, metabolic processes, catalytic activity, and apoptosis, leading to normal kidney repair. Therefore, APE1 suppressed renal fibrosis, not only via antioxidant and DNA-repair functions, but also partly by modulating the immune system through multiple pathways including Il6 , Tnf , and chemokine families. Thus, therapeutic APE1 modulation might be beneficial for the treatment of renal diseases.