Physiological mechanisms for the increase in renal solute‐free water clearance by a glucagon‐like peptide‐1 mimetic

Abstract

SUMMARY1. The aim of the present study was to clarify the mechanisms mediating the effect of a glucagon-like peptide-1 (GLP-1) mimetic on solute-free water excretion in rats.2. The GLP-1 mimetic exenatide (0.05-5.0 nmol/kg, i.m.), alone and in combination with either a vasopressin V 2 receptor antagonist (15 nmol/kg, i.p.) or vasopressin (0.01 nmol/kg, i.m.), was injected into control and water-loaded (water 10-50 mL/kg, p.o., or 50 mL/kg of 0.6% NaCl, i.p.) rats to evaluate the role of collecting duct water permeability in the hydrouretic effect. Urinary prostaglandin (PG) E 2 excretion and the effects of diclofenac (5 mg/kg, i.m.) and GLP-1 receptor antagonist (0.15 lmol/kg, i.p.) on exenatide action were assessed.3. The hydrouretic effect of exenatide was equivalent following oral or intraperitoneal water loading, and was proportional to the volume of water administered. Injection of exenatide, under conditions of a maximal decrease in collecting duct water permeability (V 2 receptor antagonist administration in waterloaded rats), additionally stimulated solute-free water formation. The GLP-1 receptor antagonist weakened the hydrouretic action of exenatide. Urinary PGE 2 excretion increased following water loading (47 AE 6 vs 24 AE 4 ng/kg over a 30 min period) and was enhanced as a result of additional exenatide injection (69 AE 10 ng/kg). Diclofenac and vasopressin delayed the hydrouretic effect of exenatide.4. The effect of exenatide on solute-free water clearance in water-loaded rats is presumably mediated by stimulation of PGE 2 secretion and reinforcement of tubular fluid influx from the proximal tubule to the distal segment of the nephron and collecting duct.

Glucagon‐like peptide‐1 acutely affects renal blood flow and urinary flow rate in spontaneously hypertensive rats despite significantly reduced renal expression of GLP‐1 receptors

“…Furthermore, GLP‐1 was able to increase free water clearance even during blockade of the V 2 receptor (Kutina et al. ).…”

Redistribution of Proximal and Distal Reabsorption of Water and Ions in Rat Kidney After Treatment with Glucagon-Like Peptide-1 Mimetic

“…Our previous experiments showed that after treatment with GLP-1 mimetic under conditions of WL, the volume of the fl uid which fl ows from the proximal tubule to the distal tubule increases due to the decrease in its reabsorption. This parameter is affected by regulatory factors in the following segments of renal tubules [8]. Urine excretion increased to 0.12±0.01 ml/min at the peak of water diuresis under the infl uence of GLP-1 mimetic.…”

“…It was interesting to evaluate the effect of this peptide on renal function during alternative shifts in water-salt balance (WSB) due to a water load (WL) or salt load (SL). Our previous experiments have demonstrated that the increase in tubular fl uid infl ow into the distal nephron segment and water-impermeable collecting duct is a component of the mechanism for excretion of water excess after treatment with GLP-1 mimetic under conditions of WL [8].…”

Ion- and osmoregulating renal functions in patients with type 2 diabetes mellitus

“…Особенное значение в этом случае имеет увели-чение притока жидкости в дистальный сегмент за счет нормализации всасывания жидкости в проксимальном сегменте нефрона. Недавно в экспериментах нами было показано, что миметик глюкагоноподобного пептида 1, эксенатид, уменьшает объем проксимальной реабсорб-ции и вызывает увеличение притока жидкости в дис-тальный сегмент нефрона и собирательные трубки [5,6]. В клинике при лечении СД2 используют эксенатид в виде препарата Баета ® (Eli Lilly).…”