The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin - induced diabetic rats is restored by 5-methyltetrahydrofolate

Abstract

Dysfunction of the endothelium is an early and key event in the development of microvascular and macrovascular complications [1], which account for most of the morbidity and mortality of diabetes. Endothelial integrity is generally assessed by evaluating the vasodilator response of a blood vessel or a vascular bed to an endothelium-dependent agonist [2]. Endothelial cells relax the tone of the underlying vascular smooth muscle cells by releasing a number of vasodi- Diabetologia (2000) Abstract Aims/hypothesis. Endothelial dysfunction contributes to the development of diabetic vascular complications. A better understanding of the pathophysiology of endothelial dysfunction in diabetes could lead to new approaches to prevent microvascular disease. Methods. Endothelium-dependent and endotheliumindependent vasodilator responses were investigated in the renal microcirculation of streptozotocin-induced diabetic rats. We measured renal blood flow changes with an electromagnetic flow probe. In addition, the responses of the different segments of the renal microcirculation were evaluated with videomicroscopy using the hydronephrotic kidney technique. Because endothelial cells release different relaxing factors (nitric oxide, prostacyclin and an unidentified endothelium-derived hyperpolarizing factor), responses to acetylcholine were measured before and after treatment with the nitric oxide synthase inhibitor l-N G -nitroarginine methylester HCI (l-NAME) and the cyclooxygenase inhibitor indomethacin. We evaluated with the effect of 5-methyltetrahydrofolate, the active form of folate, on the responses. Results. The l-NAME-and indomethacin-resistant vasodilation to intra-renal acetylcholine was significantly reduced in the diabetic compared with control rats, suggesting impaired endothelium-derived hyperpolarizing factor-mediated vasodilation. The responses to the nitric oxide donor (Z)-1-[-2-(aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate) and to the K + -channel opener pinacidil were similar in diabetics and controls, indicating intact endothelium-independent vasodilator mechanisms. The contribution of endothelium-derived hyperpolarizing factor to vasodilation induced by acetylcholine was greatest in the smallest arterioles. In diabetic rats, the response to acetylcholine was increasingly impared as vessel size decreased. Defective vasodilation in diabetic kidneys was rapidly normalized by 5-methyltetrahydrofolate. Conclusion-interpretation. Endothelium-derived hyperpolarizing factor-mediated vasodilation is impaired in the renal microcirculation of diabetic rats, in particular in the smallest arteries. Treatment with folate restores the impaired endothelial function in diabetes. [Diabetologia (2000

Glyoxalase-1 overexpression reduces endothelial dysfunction and attenuates early renal impairment in a rat model of diabetes

“…Thus, endothelial dysfunction, as an early phenomenon, may explain the typical association between albuminuria and extra-renal complications. It may be speculated that endothelial dysfunction, as we observed in the rat mesenteric arteries, is also present in the intra-renal vasculature [40,41], thereby resulting in increased pressure in the glomeruli, which consequently leads to glomerular dysfunction and urinary protein leakage. Our observations that Glo1 overexpression reduced diabetes-induced vascular and renal dysfunction, as well as data from other studies [30,42,43], support a role for glycation in these pathogeneses.…”

Acetylcholine-induced vasodilation in the perfused kidney of the streptozotocin-induced diabetic rat: role of prostacyclin

“…Indeed, in our previous studies the impairment of ACh-induced endothelium-dependent vasodilation in the diabetic perfused kidney was attributed to a decrease in NO or EDHF signaling (Kamata and Hosokawa, 1997b;Kamata and Yamashita, 1999). Moreover, there are reports of impaired NO signaling (Nangle et al, 2006) and EDHF signaling (De Vriese et al, 2000a;Nangle et al, 2006) in diabetic renal arteries.…”

Endothelium-Derived Hyperpolarizing Factor–Mediated Renal Vasodilatory Response Is Impaired During Acute and Chronic Hyperhomocysteinemia

“…The RBF response to the different agonists is expressed as the area under the curve of the change in RBF (mL/minϫmin), as detailed previously. 10,12 ANOVA and paired and unpaired t tests were used as appropriate. The significance level was set at PϽ0.05.…”

“…A blood flow sensor with an inner diameter of 0.5 to 0.7 mm was placed on the renal artery, allowing continuous renal blood flow (RBF) monitoring (T106 flowmeter, Transonic). 10,12 The RBF response to intrarenal acetylcholine (Sigma; 1 to 50 ng in bolus), to the NO donor deta-NONOate (Alexis; 16 to 80 g in bolus), and to the K ϩ -channel opener pinacidil (Sigma; 25 to 125 g in bolus) was examined. All experiments were performed in the combined presence of systemic NO synthase and cyclooxygenase blockade: N G -nitro-L-arginine methyl ester HCl (L-NAME) (Sigma; 10 mg/kg bolus followed by 20 mg/kg per hour) and indomethacin (Sigma; 4 mg/kg bolus followed by 8 mg/kg per hour).…”

“…This vascular bed is characterized by a large residual response to acetylcholine during NO synthase and cyclooxygenase inhibition, which is abolished by inhibition of gap junctional communication, indicative of a prominent EDHF pathway. 10,12 …”