AIMS: METHODS: STZ-C57BL6 mice received l-
cit or vehicle supplemented in the
drinking water. For comparative analysis, diabetic ArgII knock out mice and l-
cit-treated STZ-rats were evaluated.
RESULTS: l-
Citrulline exerted protective effects in kidneys of STZ-rats, and markedly reduced urinary
albumin excretion, tubulo-interstitial
fibrosis, and kidney
hypertrophy, observed in untreated diabetic mice. Intriguingly, l-
cit treatment was accompanied by a sustained elevation of tubular ArgII at 16 weeks and significantly enhanced plasma levels of the anti-inflammatory
cytokine IL-10. Diabetic ArgII knock out mice showed greater blood
urea nitrogen levels,
hypertrophy, and dilated tubules than diabetic wild type (WT) mice. Despite a marked reduction in
collagen deposition in ArgII knock out mice, their
albuminuria was not significantly different from diabetic WT animals. l-
Cit also restored
nitric oxide/
reactive oxygen species balance and barrier function in high
glucose-treated monolayers of human glomerular endothelial cells. Moreover, l-
cit also has the ability to establish an anti-inflammatory profile, characterized by increased
IL-10 and reduced IL-1β and IL-12(p70) generation in the human proximal tubular cells.
CONCLUSION: