Long noncoding RNAs as a determinant of microvascular stability in chronic kidney disease

Irrespective of the etiology, the common pathway in the pathology of Chronic kidney disease (CKD) involves: glomerular sclerosis, tubulointerstitial fibrosis associated with inflammation, myofibroblast proliferation and activation, extracellular matrix accumulation and tubular atrophy. The loss of the peritubular capillary network (rarefaction) is directly correlated with the severity of fibrosis, and the extent of rarefaction has been found to predict the degree of interstitial damage as well as changes in the glomerular filtration rate in CKD patients. These findings suggest an early, rate-limiting role for microvascular destabilization/loss in the pathogenesis of fibrosis.
Recent work has established that long non-coding RNAs (lncRNA) function as critical transcriptional and post-transcriptional regulators of gene expression. LncRNAs are non-protein coding RNA molecules that are minimally longer than 200 nucleotides. Based on these criteria, the human and mouse genomes have been found to express thousands of lncRNAs. However, the functions and biological relevance of but a few lncRNAs have been identified. From these studies, it has become clear that lncRNAs impact numerous key biological processes, including epigenetic regulation, alternative splicing, protein synthesis, and cell cycle control. However, a role for lncRNAs in the (patho)physiology of the kidney has yet to be investigated. Therefore, in keeping with the body of evidence indicating a critical regulatory role for microRNAs in kidney health and disease, we believe that lncRNAs are central regulators of vascular integrity in CKD. Using endothelial cell- and pericyte- lineage tracing mouse models, the aim of this study is to identify lncRNAs that are important in maintaining vascular integrity, in the context of chronic kidney disease, and to determine whether the modulation of lncRNA expression levels can influence microvascular stability.