Rat studies demonstrated that type II diabetes mellitus (T2DM) decreases both the production and bioavailability of nitric oxide (NO). L-arginine (LA) provides the precursor for the production of NO. We hypothesized that LA dietary supplementation will preserve NO production via endothelial nitric oxide synthase (eNOS) causing renal microvascular vasodilation and increased glomerular blood flow and thus increasing glomerular filtration rate (GFR). This would impede the formation of reactive oxygen species which contributes to cell damage and death. LA supplementation preserved GFR in the treated diabetic rats compared to untreated diabetic rats. We provide evidence that this effect may be due to increased levels of eNOS and urinary cyclic guanosine monophosphate, which leads to renal microvascular vasodilation. Plasma nitrotyrosine was decreased in the LA treated rats; however, plasma nitrite levels remained unaffected as expected. Marked improvements in glucose tolerance were also observed in the LA treated diabetic rats. These results demonstrate that LA supplementation preserves NO activity and may delay the onset of insulin resistance and renal dysfunction during hyperglycemic stress. These results suggest the importance of the NO pathway in consequent renal dysfunction and in the development of insulin resistance in diabetic rats. 1. Introduction Diabetic nephropathy is the number one cause of end-stage renal failure [1]. The pathogenesis of diabetic nephropathy is thought to occur in two major stages. First, there is a vasodilation in the pre- and postglomerular arterioles, which leads to higher intraglomerular blood flow and pressure. This causes an early hyperfiltration in the nephrons and eventually damages the glomerular membrane and allows for proteins, glucose, and other molecules to be filtered by the glomerulus and then excreted in the urine. Secondly, the final irreversible stage is a vasoconstriction of the glomerular arterioles, which results in low blood flow and glomerular filtration rates [2]. The nitric oxide (NO) system has been shown to be altered in diabetes and in diabetic nephropathy [3]. Nitric oxide is a vasodilator and if it is deficient or its metabolism is altered, this affects renal function and insulin sensitivity [4]. The precursor for NO is L-arginine (LA). LA is an amino acid that is synthesized within the body and can also be found in various types of food. LA is converted to NO by nitric oxide synthase (NOS) [5]. Endothelial NOS (eNOS) results in NO release from the endothelium of blood vessels and causes
References
[1]
G. Remuzzi, M. Macia, and P. Ruggenenti, “Prevention and treatment of diabetic renal disease in type 2 diabetes: the BENEDICT study,” Journal of the American Society of Nephrology, vol. 17, no. 4, supplement 2, pp. S90–S97, 2006.
[2]
T. H. Hostetter, J. L. Troy, and B. M. Brenner, “Glomerular hemodynamics in experimental diabetes mellitus,” Kidney International, vol. 19, no. 3, pp. 410–415, 1981.
[3]
M. J. Fowler, “Microvascular and macrovascular complications of diabetes,” Clinical Diabetes, vol. 26, no. 2, pp. 77–82, 2008.
[4]
C. Blouet, F. Mariotti, V. Mathe, D. Tome, and J.-F. Huneau, “Nitric oxide bioavailability and not production is first altered during the onset of insulin resistance in sucrose-fed rats,” Experimental Biology and Medicine, vol. 232, no. 11, pp. 1458–1464, 2007.
[5]
I. Buchwalow, J. Schnekenburger, K. Tiemann, et al., “L-arginine-NO-cGMP signaling pathway in pancreatitis,” Scientific Reports, vol. 3, article 1899, 2013.
[6]
F. Bourgoin, H. Bachelard, M. Badeau et al., “Endothelial and vascular dysfunctions and insulin resistance in rats fed a high-fat, high-sucrose diet,” American Journal of Physiology: Heart and Circulatory Physiology, vol. 295, no. 3, pp. H1044–H1055, 2008.
[7]
O. Shaker, N. A. Ghallab, E. Hamdy, and S. Sayed, “Inducible nitric oxide synthase (iNOS) in gingival tissues of chronic periodontitis with and without diabetes: immunohistochemistry and RT-PCR study,” Archives of Oral Biology, vol. 58, no. 10, pp. 1397–1406, 2013.
[8]
M. P. Schiaich, D. Schmitt, C. Ott, B. M. Schmidt, and R. E. Schmieder, “Basal nitric oxide synthaseactivity is a major determinant of glomerular hemodynamics in humans,” Journal of hypertension, vol. 26, no. 1, pp. 110–116, 2008.
[9]
J. Lorin, M. Zeller, J.-C. Guilland, Y. Cottin, C. Vergely, and L. Rochette, “Arginine and nitric oxide synthase: regulatory mechanisms and cardiovascular aspects,” Molecular Nutrition & Food Research, 2013.
[10]
Y. C. Luiking, G. A. T. Have, R. R. Wolfe, and N. E. Deutz, “Arginine de novo and nitric oxide production in disease states,” American Journal of Physiology: Endocrinology and Metabolism, vol. 303, no. 10, pp. E1177–E1189, 2012.
[11]
A. Jab？ecka, P. Bogdański, N. Balcer, A. Cie？lewicz, A. Sko？uda, and K. Musialik, “The effect of oral L-arginine supplementation on fasting glucose, HbA1c, nitric oxide and total antioxidant status in diabetic patients with atherosclerotic peripheral arterial disease of lower extremities,” European Review for Medical and Pharmacological Sciences, vol. 16, no. 3, pp. 342–350, 2012.
[12]
Y. Slyvka, S. R. Inman, R. Malgor et al., “Protective effects of antioxidant-fortified diet on renal function and metabolic profile in obese zucker rat,” Endocrine, vol. 35, no. 1, pp. 89–100, 2009.
[13]
K. Dutta, D. A. Podolin, M. B. Davidson, and A. J. Davidoff, “Cardiomyocyte dysfunction in sucrose-fed rats is associated with insulin resistance,” Diabetes, vol. 50, no. 5, pp. 1186–1192, 2001.
[14]
B. Betz, K. M？ller-Ehrlich, T. Kress, et al., “Increased symmetrical dimethylarginine in ischemic acute kidney injury as a causative factor of renal L-arginine deficiency,” Translational Research, vol. 162, no. 2, pp. 67–76, 2013.
[15]
S. Aiello, G. Remuzzi, and M. Noris, “Nitric oxide/endothelin balance after nephron reduction,” Kidney International Supplements, vol. 65, pp. S63–S67, 1998.
[16]
H. Toba, N. Sawai, M. Morishita et al., “Chronic treatment with recombinant human erythropoietin exerts renoprotective effects beyond hematopoiesis in streptozotocin-induced diabetic rat,” European Journal of Pharmacology, vol. 612, no. 1–3, pp. 106–114, 2009.
[17]
B. Tunctan, B. Korkmaz, A. N. Sari, et al., “Contribution of iNOS/sGC/PKG pathway, COX-2, CYP4A1, and gp91phox to the protective effect of 5, 14-HEDGE, a 20-HETE mimetic, against vasodilation, hypotension, tachycardia, and inflammation in a rat model of septic shock,” Nitric Oxide, vol. 33, pp. 18–41, 2013.
[18]
S. M. Morris Jr., T. Gao, T. K. Cooper, D. Kepka-Lenhart, and A. S. Awad, “Arginase-2 mediates diabetic renal injury,” Diabetes, vol. 60, no. 11, pp. 3015–3022, 2011.
[19]
G. Bellinghieri, D. Santoro, A. Mallamace, and V. Savica, “L-arginine: a new opportunity in the management of clinical derangements in dialysis patients,” Journal of Renal Nutrition, vol. 16, no. 3, pp. 245–247, 2006.
[20]
R. di Paola, D. Impellizzeri, P. Mondello, et al., “Palmitoylethanolamide reduces early renal dysfunction and injury caused by experimental ischemia and reperfusion in mice,” Shock, vol. 38, no. 4, pp. 356–366, 2012.
[21]
M. Peeri, M. Habibian, M. A. Azarbayjani, and M. Hedayati, “Protective effect of aerobic exercise against L-name-induced kidney damage in rats,” Archives of Industrial Hygiene and Toxicology, vol. 64, no. 2, pp. 43–49, 2013.
[22]
E. M. Awumey, L. E. Bridges, C. L. Williams, and D. I. Diz, “Nitric-oxide synthase knockout modulates Ca2+-sensing receptor expression and signaling in mouse mesenteric arteries,” The Journal of Pharmacology and Experimental Therapeutics, vol. 346, no. 1, pp. 38–47, 2013.
