Abstract
The impaired L-arginine/nitric oxide pathway is a well-recognized mechanism for cardiovascular and renal diseases with aging. Therefore, supplementation of L-arginine is widely proposed to boost health or as adjunct therapy for the patients. However, clinical data, show adverse effects and even enhanced mortality in patients receiving long-term L-arginine supplementation. The effects of long-term L-arginine supplementation on kidney aging and the underlying mechanisms remain elusive. Moreover, high protein and high amino acid diet has been thought detrimental for kidney. We therefore investigated effects of chronic dietary L-arginine supplementation on kidney aging. In both young (4 months) and old (18–24 months) mice, animals either receive standard chow containing 0.65% L-arginine or diet supplemented with L-arginine to 2.46% for 16 weeks. Inflammation and fibrosis markers and albuminuria are then analyzed. Age-associated increases in tnf-α, il-1β, and il-6, vcam-1, icam-1, mcp1, inos, and macrophage infiltration, collagen expression, and S6K1 activation are observed, which is not favorably affected, but rather further enhanced, by L-arginine supplementation. Importantly, L-arginine supplementation further enhances age-associated albuminuria and mortality particularly in females, accompanied by elevated renal arginase-II (Arg-II) levels. The enhanced albuminuria by L-arginine supplementation in aging is not protected in Arg-II−/− mice. In contrast, L-arginine supplementation increases ROS and decreases nitric oxide production in old mouse aortas, which is reduced in Arg-II−/− mice. The results do not support benefits of long-term L-arginine supplementation. It rather accelerates functional decline of kidney and vasculature in aging. Thus, the long-term dietary L-arginine supplementation should be avoided particularly in elderly population.
Highlights
L-arginine is a semi-essential amino acid involved in protein synthesis and is the substrate for nitric oxide synthase (NOS) to produce the vascular protective nitric oxide (NO) released from the endothelial cells (Wu et al, 2009)
Since L-arginine is an strong activator of mTORC1/S6K1 signaling pathway which is involved in accelerating cellular senescence and organism aging, we have analysed whether L-arginine supplementation could activate this signaling pathway and accelerate renal aging
Increased expression of aging marker p16INK4a was demonstrated in old male and female mice as compared to the young mice (Figures 4A,C), which was confirmed by immunofluorescence staining in cortex and medulla analysed by confocal microscopy (Supplementary Figure S1)
Summary
L-arginine is a semi-essential amino acid involved in protein synthesis and is the substrate for nitric oxide synthase (NOS) to produce the vascular protective nitric oxide (NO) released from the endothelial cells (Wu et al, 2009). Since decreased bioavailability of NO or deficiency of NO production promotes development of cardiovascular diseases and chronic kidney diseases, and is highly associated with aging (Schmitt and Melk, 2017; Donato et al, 2018), supplementation of L-arginine has been proposed to increase endothelial NO bioavailability and to improve health status in the young as well as in elderly population or as an adjunct therapeutic modality to treat patients with cardiovascular diseases (Creager et al, 1992). A recent Mendelian randomization study proposed that high L-arginine levels are associated with higher risk of ischemic heart disease (Au Yeung et al, 2016) which further indicates that chronic L-arginine supplementation may cause harmful effects.
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