L-citrulline protects from kidney damage in type 1 diabetic mice.

Romero, Maritza J.; Lin Yao; Sridhar, Supriya; Bhatta, Anil; Huijuan Dou; Ramesh, Ganesan; Brands, Michael W.; Pollock, David M.; Caldwell, Ruth B.; Cederbaum, Stephen D.; Head, C. Alvin; Bagi, Zsolt; Lucas, Rudolf; Caldwell, Robert W.

Rationale: Diabetic nephropathy (DN) is a major cause of end-stage renal disease, associated with endothelial dysfunction. Chronic supplementation of L-arginine (L-arg), the substrate for endothelial nitric oxide synthase (eNOS), failed to improve vascular function. L-Citrulline (L-Cit) supplementation not only increases L-arg synthesis, but also inhibits cytosolic arginase I, a competitor of eNOS for the use of L-arg, in the vasculature. Aims: To investigate whether L-Cit treatment reduces DN in streptozotocin (STZ)-induced type 1 diabetes (T1D) in mice and rats and to study its effects on arginase II (ArgII) function, the main renal isoform. 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:L-Citrulline supplementation established an anti-inflammatory profile and significantly preserved the nephron function during T1D.

CITRULLINE in the body; ANTI-inflammatory agents; DIABETIC nephropathies; NITRIC-oxide synthases; NEPHRONS; DIABETES

Frontiers in Immunology, 2013, Vol 4, p1

1664-3224

Academic Journal

10.3389/fimmu.2013.00480