Regulation of MUTYH, a DNA Repair Enzyme, in Renal Proximal Tubular Epithelial Cells

Abstract EN

MUTYH is a DNA repair enzyme that initiates a base excision repair (BER) by recognizing and removing 8-Oxoguanine (8-oxoG) and its paired adenine.

We demonstrated that both TGF-β1 and H2O2 treatment led to an increased 8-oxoG in cultured human proximal tubule epithelial (HK-2) cells, while the former induced epithelial-mesenchymal transition and the latter caused cell apoptosis.

Without stimulation, HK-2 cells showed MUTYH expression in mitochondria.

TGF-β1 triggered a transient upregulation of mitochondrial MUTYH and induced the expression of nuclear isoforms, while H2O2 showed no role on MUTYH expression.

Ureteral obstruction (UUO) mice exhibited high 8-oxoG reactivity with tubulointerstitial lesions.

After obstruction, the MUTYH expression was increased only in tubules at day 3 and decreased with obvious tubular atrophy at day 10.

Particularly, MUTYH was primarily located in normal tubular cytoplasm with a dominant mitochondrial form.

A few cells with nuclear MUTYH expression were observed in the fibrotic interstitium.

We confirmed that increased MUTYH expression was upregulated and positively correlated with the severity of kidney fibrosis.

Thus, renal fibrosis caused a cell-type-specific and time-dependent response of oxidative DNA repairs, even within the same tissues.

It suggests that intervention of MUTYH might be effective for therapies.