Pathological and molecular profiling in hypertension-induced glomerular injury

Abstract

The increased prevalence of chronic kidney disease (CKD) has become a major global health burden. This increase in CKD burden parallels the increase in hypertension prevalence. In addition, increasing evidence suggest that genetics play a strong role in the susceptibility for renal disease. Inbred mouse strains C57BL/6 and 129S6SvEv differ in their susceptibility to kidney disease when subjected to hypertension using the DOCA/salt uninephrectomy model of hypertension. Similar to others, we found the 129S6SvEv mice to be susceptible to develop severe glomerulosclerosis, whereas the C57BL/6 mice are comparatively resistant. To identify new candidate genes that are involved in the pathogenesis of glomerular disease, we used microarray technology to compare the glomerular transcriptome of both strains and determine changes in glomerular gene expression when subjected to the DOCA/salt uninephrectomy model of systemic hypertension. This approach was accompanied with ultrastructural analysis and glomerular stiffness measurements to identify corresponding structural changes. Here, we have identified novel genes associated with strain differences and hypertension, and we used immunohistochemistry to validate their expression in podocytes and glomerular arterioles in murine and human kidneys. The increased understanding of the molecular mechanisms underlying hypertension-associated podocyte injury and glomerular damage which will result from these studies, will ultimately lead to identification of novel pharmacologic targets or therapeutic strategies for patients with hypertension and renal disease.