Glucose dilates renal afferent arterioles via glucose transporter-1

Abstract

Glomerular hyperfiltration occurs during the early stage of diabetes. An acute glucose infusion increases glomerular filtration rate. The involvement of tubuloglomerular feedback response and direct effect of glucose on the afferent arterioles (Af-Arts) have been suggested. However, the signaling pathways to trigger Af-Art dilatation have not been fully identified. Therefore, in the present study we tested our hypothesis that an increase in glucose concentration enhances endothelial nitric oxide synthesis activity and dilates the Af-Arts via glucose transporter-1 (GLUT1) using isolated mouse Af-Arts with perfusion. We isolated and microperfused the Af-Arts from nondiabetic C57BL/6 mice. The Af-Arts were preconstricted with norepinephrine (1 µM). When we switched the d-glucose concentration from low (5 mM) to high (30 mM) in the perfusate, the preconstricted Af-Arts significantly dilated by 37.8 ± 7.1%, but L-glucose did not trigger the dilation. GLUT1 mRNA was identified in microdisserted Af-Arts measured by RT-PCR. Changes in nitric oxide (NO) production in Af-Art were also measured using fluorescent probe when ambient glucose concentration was increased. When the d-glucose concentration was switched from 5 to 30 mM, NO generation in Af-Art was significantly increased by 19.2 ± 6.2% (84.7 ± 4.1 to 101.0 ± 9.3 U/min). l-Glucose had no effect on the NO generation. The GLUT1-selective antagonist 4-[({[4-(1,1-Dimethylethyl)phenyl]sulfonyl}amino)methyl]- N-3-pyridinylbenzamide and the nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester blocked the high glucose-induced NO generation and vasodilation. In conclusion, we demonstrated that an increase in glucose concentration dilates the Af-Art by stimulation of the endothelium-derived NO production mediated by GLUT1.

Macula Densa SGLT1-NOS1-Tubuloglomerular Feedback Pathway, a New Mechanism for Glomerular Hyperfiltration during Hyperglycemia

“…We recently demonstrated that an increase in luminal glucose concentration dilates the mouse Af-Art by stimulation of the endothelium-derived NO production via GLUT1. 76 Another study by Toma et al 77 also showed that high glucose in vascular perfusate rather than bath solution dilates the rabbit Af-Art, which involves the local accumulation of succinate and activation of G protein-coupled metabolic receptor GPR91. Additionally, acute hyperglycemia stimulates b-cells to produce and secret insulin.…”

Update on Pathogenesis of Glomerular Hyperfiltration in Early Diabetic Kidney Disease

“…Zhang et al. used the selective GLUT1 antagonist and NOS inhibitor, respectively, to block the response of the vascular and afferent arterioles to hyperglycemia successively; it indicated that vasodilation induced by hyperglycemia is achieved through the GLUT1-mediated endothelium-dependent production of NO ( 97 ).…”

Piezo1 Mediates Vasodilation Induced by Acute Hyperglycemia in Mouse Renal Arteries and Microvessels

“…A rapid glucose-induced dilation has already been observed in mouse AA. 6 Here, we showed that hyperglycemia-induced dilation is weaker in EA than AA suggesting increased filtration pressure leading to hyperfiltration. Acute hyperglycemia did indeed increase GFR in mice, an effect that could be blocked by GsMTx4.…”

“…NO production in isolated AA and HUVECs was measured using the cell-permeable fluorescent NO indicators 4,5-diaminofluorescein diacetate and 3-amino, 4-aminomethyl-2′,7′-difluorofluorescein diacetate, respectively, as described previously. 6…”

“…Afferent arterioles (AA) dilate in response to acute hyperglycemia and this may increase glomerular filtration rate. 6 Increased glomerular perfusion, transcapillary hydraulic pressure difference, and permeability may lead to structural lesions of glomeruli and tubuli. 7 Remarkably, vascular beds of different organs respond differently to acute hyperglycemia showing improved as well as impaired endothelial function.…”