Arginine metabolism regulates the transcription factor Nrf2 and prevents renal interstitial fibrosis.

Abstract

All chronic inflammation of the kidney leads to end stage renal failure via renal interstitial fibrosis. In diabetic nephropathy, changes in renal glucose metabolism have been noted to affect interstitial fibrosis. However, the effects of other metabolic pathways on renal interstitial fibrosis are not clear.

To find the metabolic pathways that are altered in renal interstitial fibrosis, we performed metabolomic analysis using a mouse model of unilateral ureteral obstruction (UUO). The pathway of arginine and proline metabolism, and arginine biosynthesis were significantly enhanced in UUO mice. Therefore, we focused on arginase 2 (ARG2), a key enzyme in arginine metabolism.

In UUO mice, ARG2 and spermidine, a degradation product of L-arginine by ARG2, was increased in the renal tubules. When the UUO model was created using Arg2 knockout (KO) mice, renal interstitial fibrosis was significantly exacerbated in Arg2 KO mice. Arg2 KO kidneys were expected to have high inflammation, but the antioxidant transcription factor Nrf2 was reduced, and the expression of the target gene HO-1 was also decreased. To investigate arginine metabolism and Nrf2 activation, spermidine was added to human renal tubule HK-2 cells, and nuclear translocation of Nrf2 was strongly induced. ARG2 is increased in tubules during renal interstitial fibrosis, was predicted to exert its nephroprotective effect by activating Nrf2 through its metabolite spermidine.