GSE159059
Gene expression profiles of diabetic kidney disease and neuropathy in eNOS knockout mice: predictors of pathology and RAAS blockade effects
Diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) are two common diabetic complications. However, their pathogenesis remains elusive and current therapies are only modestly effective. We evaluated genome-wide expression to identify pathways involved in DKD and DPN progression in db/db eNOS -/- mice receiving renin-angiotensin-aldosterone system (RAAS) blocking drugs to mimic the current standard of care for DKD patients. Diabetes and eNOS deletion worsened DKD, which improved with RAAS treatment. Diabetes also induced DPN, which was not affected by eNOS deletion or RAAS blockade. Given the multiple factors affecting DKD and the graded differences in disease severity across mouse groups, an automatic data-analysis method, SOM or self-organizing map was used to elucidate glomerular transcriptional changes associated with DKD, whereas pairwise bioinformatics analysis was used for DPN. These analyses revealed that enhanced gene expression in several pro-inflammatory networks and reduced expression of development genes correlated with worsening DKD. Although RAAS treatment ameliorated the nephropathy phenotype, it did not alter the more abnormal gene expression changes in kidney. Moreover, RAAS exacerbated expression of genes related to inflammation and oxidant generation in peripheral nerves. The graded increase in inflammatory gene expression and decrease in development gene expression with DKD progression underline the potentially important role of these pathways in DKD pathogenesis. Since RAAS blockers worsened this gene expression pattern in both DKD and DPN, it may partly explain the inadequate therapeutic efficacy of such blockers. Overall design: Identification of transcriptional pathways involved in progression of db/db eNOS mice receiving RAAS blocking drugs