Using gene chips to identify organ-specific, smooth muscle responses to experimental diabetes: potential applications to urological diseases

Abstract

Objective: To identify early diabetes-related alterations in gene expression in bladder and erectile tissue that would provide novel diagnostic and therapeutic treatment targets to prevent, delay or ameliorate the ensuing bladder and erectile dysfunction.

Materials and methods: The RG-U34A rat GeneChip (Affymetrix Inc., Sunnyvale, CA, USA) oligonucleotide microarray (containing approximately 8799 genes) was used to evaluate gene expression in corporal and male bladder tissue excised from rats 1 week after confirmation of a diabetic state, but before demonstrable changes in organ function in vivo. A conservative analytical approach was used to detect alterations in gene expression, and gene ontology (GO) classifications were used to identify biological themes/pathways involved in the aetiology of the organ dysfunction.

Results: In all, 320 and 313 genes were differentially expressed in bladder and corporal tissue, respectively. GO analysis in bladder tissue showed prominent increases in biological pathways involved in cell proliferation, metabolism, actin cytoskeleton and myosin, as well as decreases in cell motility, and regulation of muscle contraction. GO analysis in corpora showed increases in pathways related to ion channel transport and ion channel activity, while there were decreases in collagen I and actin genes.

Conclusions: The changes in gene expression in these initial experiments are consistent with the pathophysiological characteristics of the bladder and erectile dysfunction seen later in the diabetic disease process. Thus, the observed changes in gene expression might be harbingers or biomarkers of impending organ dysfunction, and could provide useful diagnostic and therapeutic targets for a variety of progressive urological diseases/conditions (i.e. lower urinary tract symptoms related to benign prostatic hyperplasia, erectile dysfunction, etc.).

FIG. 1

Schematic depiction of the algorithm used for identifying differentially expressed genes, as well as for illustrating prominent biological themes and pathways. BSM, bladder smooth muscle; CSM, corporal smooth muscle; DBSM, diabetic-bladder smooth muscle; DCSM, diabetic-corporal smooth muscle.

FIG. 2

GenMapp pathway showing the impact of 1 week of STZ-DM on transcription in pathways involved in myocyte contraction and relaxation. Although this pathway was specifically developed for the myometrium, there is enough transcriptional overlap in the relevant pathways with the detrusor and corporal myocyte to make this a useful illustrative tool.

FIG. 3

GenMapp pathway showing the impact of 1 week of STZ-DM on transcription in pathways involved in regulation of the actin cytoskeleton. Again, although this pathway was not specifically developed for the detrusor or corporal myocyte, there is enough transcriptional overlap to make this a useful illustrative tool.

FIG. 4

GenMapp pathway showing the impact of 1 week of STZ-DM on transcription in pathways related to cytokines and the inflammatory response. Again, although this pathway was not specifically developed for the detrusor or corporal myocyte, there is enough transcriptional overlap to make this a useful illustrative tool.

FIG. 5

GenMapp pathway showing the impact of 1 week of STZ-DM on transcription in pathways involved in calcium regulation. Although this pathway was specifically developed for the myocardium, there is enough transcriptional overlap in the relevant pathways with the detrusor and corporal myocyte to make this a useful illustrative tool.