Arginase 1 mediates increased blood pressure and contributes to vascular endothelial dysfunction in deoxycorticosterone acetate (DOCA)-salt hypertension

Enhanced arginase (ARG) activity has been identified as a factor that reduces nitric oxide (NO) production and impairs endothelial function in vascular pathologies. Using a gene deletion model, we investigated involvement of arginase isoforms (1 and 2) in hypertension and endothelial dysfunction in a mineralocorticoid-salt mouse model. Hypertension was induced in wild type (WT), partial ARG1+/- knockout (KO) and complete ARG2-/- KO mice by uninephrectomy and DOCA-salt treatment for 6-weeks. (Control uninephrectomized mice drank tap water). After 2 wks of DOCA-salt treatment, systolic blood pressure (SBP) was increased by ~15 mmHg in all mouse genotypes. SBP continued to rise in DOCA-salt WT and ARG2-/- mice to ~130 mmHg at 5-6 wks, whereas in ARG1+/- mice SBP waned toward control levels by 6 wks (109±4 vs 101±3 mmHg, respectively). DOCA-salt treatment in WT mice increased vascular ARG activity (aorta by 1.5-fold; mesenteric artery (MA) by 2.6-fold and protein levels of ARG1 (aorta: 1.49-fold and MA: 1.73-fold) versus WT Sham tissues. ARG2 protein increased in WT DOCA MA (by 2.15-fold) but not in aorta compared to those of WT Sham tissues. Maximum endothelium-dependent vasorelaxation to acetylcholine was significantly reduced in DOCA-salt WT mice and largely or partially maintained in DOCA ARG1+/- and ARG2-/- mice vs their Sham controls. DOCA-salt augmented contractile responses to phenylephrine in aorta of all mouse genotypes. Additionally, treatment of aorta or MA from WT DOCA mice with arginase inhibitor ABH (100 µM) improved endothelium-mediated vasorelaxation. DOCA-salt induced coronary perivascular fibrosis (increased by 2.1-fold) in WT was prevented in ARG1+/- and reduced in ARG2-/- mice. In summary, arginase is involved in murine DOCA-salt induced impairment of vascular function and hypertension and may represent a novel target for antihypertensive therapy

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

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. 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. 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-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. Conclusions. L-cit supplementation established an anti-inflammatory profile and significantly preserved the nephron function during type 1 diabetes. <br/