Differential expression of renal AGE-receptor genes in NOD mice: Possible role in nonobese diabetic renal disease

Background. Nonobese diabetic mice (NOD) are prone to glomerular pathology, which is accelerated with the onset of diabetes. Advanced glycation end pr oduct (AGE) interactions with AGE-receptors (AGE-Rs) in kidneys can contrib ute to glomerular injury and diabetic nephropathy (DN). The significant ele vation in kidney AGE deposits noted in prediabetic NOD mice suggested that delayed AGE turnover in this model may contribute to its propensity toward DN. Methods. To explore whether excess tissue AGE was linked to altered AGE-R s tatus in the kidney, mRNA/protein expression, and of several AGE-Rs [AGE-R1 , AGE-R2, AGE-R3, scavenger receptor II (ScR-II), and receptor for AGE (RAG E)], was determined in renal cortex and in mesangial cells (MCs) isolated f rom ND-, D-NOD, and ILE mice (N = 20 per group). Ligand binding, receptor s ite number, and affinity were determined in MCs from the same mouse groups. Results. Prediabetic NOD kidney AGE-Ri mRNA and protein level were threefol d lower than that of ILE mice (P < 0.01), while AGE-R3 mRNA was enhanced by twofold (P < 0.05) and AGE-R2, RAGE, and ScR-II mRNA remained close to nor mal (ILE). The onset of diabetes in NOD mice, while enhancing AGE-Ri mRNA e xpression by approximately twofold, failed to raise it above the normal (IL E) level, despite increases in tissue, and serum AGE. The latter was associ ated with higher elevation in AGE-R3 (sixfold, P < 0.05), RAGE (twofold, P = NS), and ScR-II mRNA (2.8-fold, P = NS) above control. MCs from prediabet ic NOD mice showed a threefold lower level of AGE-Ri mRNA (P < 0.02 vs. ILE ) and AGE-R1-protein, and AGE-binding activity (< 40% of control ILE). In c ontrast, AGE-R3 mRNA was enhanced (twofold), while AGE-R2 showed no change. Cultured ND-NOD MCs displayed only one fourth of the AGE-binding sites/cel l present on ILE MCs (1.6 X 10(6) vs. 6.6 X 10(6), P < 0.05), which after t he onset of diabetes rose to the normal range (7.0 X 10(6)/ cell), but fail ed to exceed it. Conclusions. Reduced AGE-Ri gene expression in this strain may contribute t o delayed AGE removal from and early AGE deposition in kidney tissues. This may act as a trigger for those AGE-R genes involved in growth-promoting ch anges, leading to DN in this strain.