Abstract
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.
Highlights
Patients with Type 1 diabetes (T1D) have a considerably worse long-term prognosis than individuals without diabetes, due to the high incidence of cardiovascular disease and end-stage renal disease (ESRD)
Diabetic arginase II (ArgII) knock out mice showed greater blood urea nitrogen levels, hypertrophy, and dilated tubules than diabetic wild type (WT) mice
ArgII has been proposed to be a mediator of Diabetic nephropathy (DN) [22], we observed a significant greater kidney size and blood urea nitrogen (BUN) levels in the ArgII knock out mice, as compared to diabetic WT animals (Table 2)
Summary
Patients with Type 1 diabetes (T1D) have a considerably worse long-term prognosis than individuals without diabetes, due to the high incidence of cardiovascular disease and end-stage renal disease (ESRD). Diabetic nephropathy (DN), the leading cause of chronic kidney disease in the United States, is responsible for up to 40% of all ESRD cases [1]. Since conventional or recently proposed therapies toward DN are still under ongoing investigation, or lack major efficacy, the search for novel targets involved in diabetes-induced renal damage is of primary importance. It is generally recognized that dysfunction of endothelial nitric oxide synthase (eNOS) contributes to vascular pathology in diabetes. An important cause of impaired endothelial nitric oxide (NO) production is the reduced availability of the eNOS substrate www.frontiersin.org. Patients with diabetes and cardiovascular disease were shown to benefit from acute l-arg supplementation [2], but chronic l-arg therapy caused adverse effects [3]
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