Spermidine from arginine metabolism activates Nrf2 and inhibits kidney fibrosis

Abstract

Kidney metabolism may be greatly altered in chronic kidney disease. Here we report that arginine metabolism is the most altered in unilateral ureteral obstruction (UUO)-induced fibrosis of the kidneys in metabolomic analysis. Spermidine is the most increased metabolite of arginine. In human glomerulonephritis, the amount of spermidine shown by immunostaining is associated with the amount of fibrosis. In human proximal tubule cells, spermidine induces nuclear factor erythroid 2-related factor 2 (Nrf2). Subsequently, fibrotic signals, such as transforming growth factor β1 secretion, collagen 1 mRNA, and oxidative stress, represented by a decrease in the mitochondrial membrane potential is suppressed by spermidine. UUO kidneys of Arg2 knockout mice show less spermidine and significantly exacerbated fibrosis compared with wild-type mice. Nrf2 activation is reduced in Arg2 knockout UUO kidneys. Spermidine treatment prevents significant fibrotic progression in Arg2 knockout mice. Spermidine is increased in kidney fibrosis, but further increases in spermidine may reduce fibrosis.

Polyamines in Ovarian Aging and Disease

“…Previous studies have shown that the activation of the Nrf2 signaling pathway or the oxidative stress inhibitor NAC can increase telomerase expression and activity, preserve the number of primordial follicles, and improve the quality of oocytes in old mice [62,63]. Interestingly, spermidine can activate the Nrf2 signaling pathway, increase the activity of antioxidant enzymes and alleviate oxidative stress [37,64]. Therefore, spermidine may preserve telomere length and prevent ovarian aging by attenuating oxidative stress.…”