Biogenesis, Stabilization, and Transport of microRNAs in Kidney Health and Disease

Abstract

The kidneys play key roles in the maintenance of homeostasis, including fluid balance, blood filtration, erythropoiesis and hormone production. Disease-driven perturbation of renal function therefore has profound pathological effects, and chronic kidney disease is a leading cause of morbidity and mortality worldwide. Successive annual increases in global chronic kidney disease patient numbers in part reflect upward trends for predisposing factors, including diabetes, obesity, hypertension, cardiovascular disease and population age. Each kidney typically possesses more than one million functional units called nephrons, and each nephron is divided into several discrete domains with distinct cellular and functional characteristics. A number of recent analyses have suggested that signaling between these nephron regions may be mediated by microRNAs. For this to be the case, several conditions must be fulfilled: (i) microRNAs must be released by upstream cells into the ultrafiltrate; (ii) these microRNAs must be packaged protectively to reach downstream cells intact; (iii) these packaged microRNAs must be taken up by downstream recipient cells without functional inhibition. This review will examine the evidence for each of these hypotheses and discuss the possibility that this signaling process might mediate pathological effects.

Exosomal mitochondrial tRNAs and miRNAs as potential predictors of inflammation in renal proximal tubular epithelial cells

“…We also found that the highly abundant and significantly dysregulated exosomal miRNAs (i.e., hsa-miR-192-5p, -21-5p, -215-5p, À200b-3p, and À200c-3p) were upregulated in cytokine-induced exosomes, an observation that is consistent with in vivo studies of acute kidney injury and diabetic nephropathy, the leading cause of CKD. 93,94,97 Interestingly, by comparing differentially expressed exosomal miRNAs from cytokine-stimulated RPTECs with urinary exosomal miRNAs from clinical CKD patient samples and controls (N = 25), as previously reported by our group, 19 we found that eight out of 30 exosomal miRNA species differentially expressed in cytokine-stimulated RPTECs were also differentially expressed in the urinary exosomes derived from different CKD stages (Table S5). The dysregulated exosomal miRNAs (i.e., hsa-miR-215-5p, hsa-miR-192-5p, hsa-miR-146a-5p, hsa-miR-23b-3p, hsa-miR-126-5p, hsa-miR-126-3p, hsa-miR-21-5p, and hsa-miR-31-3p) mostly represent an early stage of CKD, i.e., stage II, followed by stage IV, stage III, and then stage I (Table S5).…”

“…92 In kidney cells, signaling between nephron regions can be mediated by miRNAs derived from EVs (i.e., exosomes). 93 In kidney injury, some miRNAs (e.g., miR-21, miR-126, miR-146a, and miR-200 family) have protective effects (e.g., antiapoptosis, anti-inflammation, and anti-fibrosis), while some miRNAs (e.g., miR-21 and miR-192) elicit pathological influence by promoting apoptosis, inflammation, and fibrosis. 94 Thus, we speculate that the release of highly abundant exosomal miRNAs, which we observed to be common to both the non-stimulated and stimulated conditions, might be essential for maintenance of cellular homeostasis in normal proximal tubule cell type and/or recipient cells, and that their altered abundance in response to cytokine stimulation might promote inflammation and the development of CKD.…”

microRNA Crosstalk Influences Epithelial-to-Mesenchymal, Endothelial-to-Mesenchymal, and Macrophage-to-Mesenchymal Transitions in the Kidney

“…Differential miRNA expression data suggest a role of altered miRNA in the pathogenesis of kidney disease (Bhatt et al, 2011; Lorenzen et al, 2011; Zhong et al, 2011; Chau et al, 2012; Chung and Lan, 2015; Van Der Hauwaert et al, 2015; Schauerte et al, 2017; Zhang et al, 2017; Hajarnis et al, 2018; Thomas et al, 2018; Xi et al, 2018; Yang et al, 2018; Zheng et al, 2018; Fujii et al, 2019; Liu et al, 2019a; Liu et al, 2019c; Zhao et al, 2019). The term fibromiR has been suggested for those miRNAs that regulate fibro-proliferative diseases (Pottier et al, 2014).…”

MicroRNAs and their delivery in diabetic fibrosis

“…More specifically, miRNAs have been implicated in the fibrosis of organ systems covered in more detail elsewhere in this volume including diabetic retinopathy [27][28][29], diabetic cardiomyopathy [30,31], diabetic liver fibrosis [32,33] and diabetic pulmonary fibrosis [34]. Key miRNA functions also modulate kidney development and maintenance of homeostasis, as well as driving the pathology of numerous renal diseases including diabetic kidney disease (DKD) [35][36][37][38][39][40][41][42].…”