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

By Maritza J Romero, Maritza J Romero, Maritza J Romero, Lin eYao, Supriya eSridhar, Anil eBhatta, Huijuan eDou, Ganesan eRamesh, Ganesan eRamesh, Michael W Brands, David M Pollock, David M Pollock, Ruth B Caldwell, Ruth B Caldwell, Ruth B Caldwell, Stephen D Cederbaum, C Alvin eHead, Zsolt eBagi, Rudolf eLucas, Rudolf eLucas, Rudolf eLucas and Robert William Caldwell and Robert William Caldwell


Rationale. Diabetic nephropathy 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 (Arg I), a competitor of eNOS for the use of L-arg, in the vasculature. <br/>Aims. To investigate whether L-cit treatment reduces diabetic nephropathy in streptozotocin (STZ)-induced type 1 diabetes in mice and rats and to study its effects on arginase II (ArgII) function, the main renal isoform. <br/>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. <br/>Results. L-cit 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 wks and significantly enhanced plasma levels of the anti-inflammatory cytokine IL-10. Diabetic ArgII knock out mice showed greater BUN levels, hypertrophy, and dilated tubules than diabetic wild type mice. Despite a marked reduction in collagen deposition in ArgII knock out mice, their albuminuria was not significantly different from diabetic wild type animals. L-cit also restored NO/ROS 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-1beta and IL-12(p70) generation in the human proximal tubular cells. <br/>Conclusions. L-cit supplementation established an anti-inflammatory profile and significantly preserved the nephron function during type 1 diabetes. <br/

Topics: Arginase, IL-10, diabetic nephropathy, L-citrulline, glomerulosclerosis, Immunologic diseases. Allergy, RC581-607
Publisher: Frontiers Media S.A.
Year: 2013
DOI identifier: 10.3389/fimmu.2013.00480
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