Background The Receptor of Advanced Glycation end Products (RAGE) has been shown to interact with caveolin-rich membrane domains in the retinal microvascular endothelium of culture cells. Our preliminary data identified an interaction between the mineralocorticoid receptor (MR), RAGE and caveolin-1 (Cav-1) in kidney tissue.
Objective To determine that RAGE-MR-Cav-1 relationship might play a role in diabetic nephropathy.
Design and Methods Three groups of uninephrectomized, Wistar rats were randomized in three groups: 1) control, n = 10; 2) streptozotocin (STZ), n = 11; and 3) STZ + eplerenone (administered in the rat chow), n = 16. All rats received rat chow containing 1.6% Na+ and 1.1% K+. Diabetes mellitus (DM) was induced by a single dose of STZ. Rats were sacrificed on day 28. Confocal microscopy and immunocoprecipitation techniques were employed to determine colocalization of MR, RAGE, and Cav-1 in the kidney. Western blot analysis was used to determine protein levels. Rat urine albumin was measured using an enzyme immunoassay.
Results RAGE colocalizes with MR and Cav-1 in kidney vessels. Eplerenone treatment diminished this colocalization. Immunoprecipitation of RAGE and detection of MR or caveolin-1 was significantly different (p < .05), (p < .01) (mean ± SE) 1.6 ± 0.09, 0.5 ± 0.04, 1.3 ± 0.04, 0.81 ± 0.1 in STZ and STZ/eplerenone groups, respectively. Day 28 systolic tailcuff blood pressures (BP) were not significantly different in the STZ (BP = 123 ± 2 mm Hg) and STZ/eplerenone (BP = 117 ± 2 mm Hg) groups. Day 28 systolic BP was significantly (p < .001) higher in the STZ group as compared to the control group, BP = 109 ± 3 mm Hg. Kidney weight and kidney/body weight measurements were significantly (p < .001) elevated in the STZ groups compared to the control group. The STZ/eplerenone group had significantly (p < .01) lower kidney weights and kidney/body weight ratios and significantly (p < .05) lower proteinuria compared to the STZ group.
Conclusion RAGE interacts with MR and Cav-1 in kidney vasculature. Eplerenone reduces RAGE-MR and RAGE-Cav-1 colocalization, proteinuria and kidney hypertrophy in this early model of type 1 DM. This suggests that the MR-RAGE-Cav-1 relationship plays a role in the early pathogenesis of diabetic nephropathy.