Glucagon and glucagon-like peptide-1 (GLP-1) are structurally related peptides produced by post-translational tissue-specific processing of the proglucagon gene product. These peptides are known to play a role in glucose homeostasis. The glucagon receptor and GLP-1 receptor have both been found in the kidney, but the sites of their expression have not been determined. Using nephron microdissection and RT-PCR, we have studied the distribution of the mRNA of these receptors throughout the renal tubule and the effect of diabetes on the level of their expression.

Diabetes was induced in male Sprague-Dawley rats using a single tail-vein injection of streptozotocin (45 mg kg^-1). Three weeks after induction of diabetes rats were terminally anaesthetized with pentobarbitone sodium (90 mg kg^-1 I.P.) and the left kidney perfused with microdissection solution containing 0.24 % (w/v) collagenase. Nephron segments were microdissected from control and diabetic kidney and RNA extracted using the phenol/chloroform method. RT-PCR was carried out using a 1 mm length of tubule per reaction and intron spanning gene specific primers designed to GR and GLP-1R. Experiments were performed in accordance with the Animals (Scientific Procedures) Act 1986.

GR mRNA was present in all nephron segments tested with the highest expression in the thick ascending limb (TAL). In contrast GLP-1R was only detected in the proximal convoluted tubule (PCT). Three-week diabetes resulted in a 56 and 71 % increase in the mRNA levels of GR in the PCT and TAL, respectively (n = 5, P < 0.05, Student’s unpaired t test), but remained at a constant level in other nephron segments. The pattern of expression of GLP-1R was unchanged by diabetes, although there was a 53 % decrease in the mRNA levels in the PCT (n = 5, P < 0.001).

Our results show that diabetes differentially regulates the expression of GR and GLP-1 mRNA. It is of interest to note that rat pancreatic islets cultured in high glucose concentrations also show an increase in GR and a decrease in GLP-1R mRNA (Abrahamsen & Nishimura, 1995). Expression of GLP-1 exclusively in the PCT may indicate a role in glucose sensing, as seems to be the case in rat hypothalamic cells (Navarro et al. 1996). Since GR activation in the TAL is known to stimulate Na⁺ reabsorption (De Rouffignac et al. 1991), and since glucagon promotes GLUT-mediated glucose transport in the proximal tubule (Marks et al. 1998), an increase in plasma glucagon concentration and GR mRNA may contribute to enhanced glucose and Na⁺ reabsorption during diabetes.

We are grateful to The Wellcome Trust and to the St Peters Trust, Middlesex Hospital, for support.