Gene expression profiling in glomeruli from human kidneys with diabetic nephropathy

Diabetic nephropathy (DN) is a frequent complication in patients with diabetes mellitus. To find improved intervention strategies in this disease, it is necessary to investigate the molecular mechanisms involved. To obtain more insight into processes that lead to DN, messenger RNA expression profiles of diabetic glomeruli and glomeruli from healthy individuals were compared.

Two morphologically normal kidneys and 2 kidneys from patients with DN were used for the study. Glomerular RNA was hybridized in duplicate on Human Genome U95Av2 Arrays (Affymetrix, Santa Clara, CA). Several transcripts were tested further in independent patient groups and at the protein level by immunohistochemistry.

Ninety-six genes were upregulated in diabetic glomeruli, whereas 519 genes were downregulated. The list of overexpressed genes in DN includes aquaporin 1, calpain 3, hyaluronoglucosidase, and platelet/endothelial cell adhesion molecule. The list of downregulated genes includes bone morphogenetic protein 2, vascular endothelial growth factor (VEGF), fibroblast growth factor 1, insulin-like growth factor binding protein 2, and nephrin. A decrease in VEGF and nephrin could be validated at the protein level and also at the RNA level in renal biopsy specimens from 5 additional patients with diabetes.

Results of oligonucleotide microarray analyses on control and diabetic glomeruli are presented and discussed in their relation to vascular damage, mesangial matrix expansion, proliferation, and proteinuria. Our findings suggest that progression of DN might result from diminished tissue repair capability.