Abstract
There is an increasing prevalence of chronic kidney disease (CKD), which associates with the development of interstitial fibrosis. Pericytes (perivascular fibroblasts) provide a major source of α-SMA-positive myofibroblasts that are responsible for the excessive deposition of extracellular matrix. In order to identify pericyte long non-coding RNAs (lncRNAs) that could serve as a target to decrease myofibroblast formation and counteract the progression of kidney fibrosis we employed two models of experimental kidney injury, one focused on kidney fibrosis (unilateral ureteral obstruction; UUO), and one focused on acute kidney injury that yields kidney fibrosis in the longer term (unilateral ischemia-reperfusion injury; IRI). This was performed in FoxD1-GC;tdTomato stromal cell reporter mice that allowed pericyte fate tracing. Tomato red-positive FoxD1-derivative cells of control and injured kidneys were FACS-sorted and used for lncRNA and mRNA profiling yielding a distinctive transcriptional signature of pericytes and myofibroblasts with 244 and 586 differentially expressed lncRNAs (>twofold, P < 0.05), in the UUO and IRI models, respectively. Next, we selected two differentially expressed and conserved lncRNAs, Rian (RNA imprinted and accumulated in nucleus) and Miat (Myocardial infarction associated transcript), and explored their potential regulatory role in myofibroblast formation through knockdown of their function with gapmers. While Miat was upregulated in myofibroblasts of UUO and IRI in mice, gapmer silencing of Miat attenuated myofibroblast formation as evidenced by decreased expression of α-SMA, col1α1, SMAD2, and SMAD3, as well as decreased α-SMA and pro-collagen-1α1 protein levels. In contrast, silencing Rian, which was found to be downregulated in kidney myofibroblast after IRI and UUO, resulted in increased myofibroblast formation. In addition, we found microRNAs that were previously linked to Miat (miR-150) and Rian (14q32 miRNA cluster), to be dysregulated in the FoxD1-derivative cells, suggesting a possible interaction between miRNAs and these lncRNAs in myofibroblast formation. Taken together, lncRNAs play a regulatory role in myofibroblast formation, possibly through interacting with miRNA regulation, implicating that understanding their biology and their modulation may have the potential to counteract the development of renal fibrosis.
Highlights
Chronic kidney disease (CKD) has an estimated worldwide prevalence of about 8% (Hallan et al, 2009; Bruck et al, 2016) and, due to the increasing prevalence of non-communicable diseases such as diabetes and hypertension, the numbers of patients are ever increasing (United States Renal Data System’s Annual Data Report, 2010)
We demonstrated that the pericyte long non-coding RNAs (lncRNAs) expression profile is strongly altered upon myofibroblast formation in of kidney fibrosis
This loss of the peritubular capillary network 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 chronic kidney disease (CKD) patients (Seron et al, 1990; Choi et al, 2000)
Summary
Chronic kidney disease (CKD) has an estimated worldwide prevalence of about 8% (Hallan et al, 2009; Bruck et al, 2016) and, due to the increasing prevalence of non-communicable diseases such as diabetes and hypertension, the numbers of patients are ever increasing (United States Renal Data System’s Annual Data Report, 2010). Irrespective of the etiology, the common pathway in the pathology of CKD involves the development of tubulointerstitial fibrosis characterized by myofibroblast proliferation and subsequent excessive extracellular matrix accumulation (Levey and Coresh, 2012). It has been previously demonstrated that pericytes (or perivascular fibroblasts), are the major source of myofibroblasts in renal fibrosis (Humphreys et al, 2010). Recent work has established that long non-coding RNAs (lncRNA) function as novel critical transcriptional and posttranscriptional regulators of gene expression. A role for lncRNAs in the (patho)physiology of kidney fibrosis is only recently emerging. LncRNA Erbb4-IR was found to promote renal fibrosis by targeting miR-29b (Sun et al, 2018) while other studies demonstrated that inhibition of Linc00963 and H19 were protective against renal fibrosis (Xie et al, 2016; Chen et al, 2018)
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