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

Abstract

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.

Uromodulin aggravates renal tubulointerstitial injury through activation of the complement pathway in rats

“…Our study showed that UUO rats sustained severe renal tubular injury, based on the results from the staining. The development of tubulointerstitial fibrosis in the kidney may occur via oxidative stress secondary to ureteral obstruction (Maruyama et al, 2019). Our data indicated that UUO rats have downregulated levels of Umod.…”

A Dual Face of APE1 in the Maintenance of Genetic Stability in Monocytes: An Overview of the Current Status and Future Perspectives

“…Additionally, it was also proved that APE1 is secreted from monocytes after LPS treatment, and then, this extracellular APE1 localizes on the cell surface of the next primary monocyte cell membranes and modulates its inflammatory response [93]. All this suggests that through this mechanism, AP endonuclease may modulate local inflammation and mobilize the next immune cells [116,117]. However, this role of APE1 is particularly interesting in the context of the radiotherapy described above.…”

Inducible deletion of microRNA activity in kidney mesenchymal cells exacerbates renal fibrosis

“…The 8–12 week-old Dicer cKO mice (n = 9) and control mice (n = 9) underwent UUO via cauterization of the ureter, as described previously 20 , 21 . Briefly, male mice were anesthetized with isoflurane and placed in an abdominal position at a controlled body temperature.…”

“…Interstitial fibrosis was quantified as Sirius red-positive areas, as described previously 20 . Tissue preparation for histological staining of cryosections was performed as previously described 21 . Briefly, the collected kidneys were fixed with 4% paraformaldehyde for 2 h, washed in 18% sucrose solution overnight, and embedded in FSC 22 Clear Frozen Section Compound (Leica Biosystems).…”