β‐catenin‐controlled tubular cell‐derived exosomes play a key role in fibroblast activation via the OPN‐CD44 axis

Abstract

Tubular injury and peripheral fibroblast activation are the hallmarks of chronic kidney disease (CKD), suggesting intimate communication between the two types of cells. However, the underlying mechanisms remain to be determined. Exosomes play a role in shuttling proteins and other materials to recipient cells. In our study, we found that exosomes were aroused by β‐catenin in renal tubular cells. Osteopontin (OPN), especially its N‐terminal fragment (N‐OPN), was encapsulated in β‐catenin‐controlled tubular cell‐derived exosome cargo, and subsequently passed to fibroblasts. Through binding with CD44, exosomal OPN promoted fibroblast proliferation and activation. Gene deletion of β‐catenin in tubular cells (Ksp‐β‐catenin −/− ) or gene ablation of CD44 (CD44 −/− ) greatly ameliorated renal fibrosis. Notably, N‐OPN was carried by exosome and secreted into the urine of patients with CKD, and negatively correlated with kidney function. The urinary exosomes from patients with CKD greatly accelerated renal fibrosis, which was blocked by CD44 deletion. These results suggest that exosome‐mediated activation of the OPN/CD44 axis plays a key role in renal fibrosis, which is controlled by β‐catenin.

Identification and analysis of the predictive urinary exosomal miR-195-5p in lupus nephritis based on renal miRNA-mRNA co-expression network

“…As the main executor of reabsorption and re-secretion, the applications of tubular cell-derived exosomes in acute kidney injury and diabetic nephropathy have been reported in few studies. 38,39 Tubular-derived exosomes were the main and functional component of urinary exosomes, 40 we first screened credible changed miRNAs in tubular cells by miRNA-mRNA integrated analysis and verified whether these changes really exist in patients’ urine samples so that we can identify the consistent changed miRNAs in both LN biopsy tissues and urinary samples. In reported exosomal miRNAs, we found miR-26a was increased (line 9 in Figure 1(a)) while miR-29c (line 42) and let-7a (line 45) were downregulated in the LN kidney miRNA profiles.…”

The role of extracellular vesicles in vascular calcification in chronic kidney disease

“…The methylation-modified RNA-binding protein YBX1 promotes lung cancer proliferation and metastasis by regulating oncogenic factors in EVs-related fragments ( 18 ). Similarly, β-catenin in renal tubular cells is caused by exosomes, and genetic deletion of this protein greatly ameliorates renal fibrosis ( 19 ). In the mid-1960s, Bonucci reported the involvement of EVs in the calcification process ( 20 ).…”

CD44 promotes angiogenesis in myocardial infarction through regulating plasma exosome uptake and further enhancing FGFR2 signaling transduction

“…have been well demonstrated for the identification of exosomes (Kalluri and LeBleu 2020 ). CD44, which was reported to be an important regulator in membrane organization (Kumar et al 2022 ; Wei et al 2014 ), may play an essential role in the biogenesis and functional regulation of exosomes (Chen et al 2022 ; Kelemen et al 2022 ; Shen et al 2021 ). CD44 was found to be widely expressed in stem cells, monocytes, tumor cells, and vascular endothelial cells (ECs), and it participates in the pathological process under ischemic conditions (Chen et al 2020 ).…”

“…Of note, the distribution and endocytosis of CD44, associated with CD9-positive tetraspanin-enriched microdomains and lipid rafts in microvascular ECs, present potential functional connections between CD44 and the membrane reorganization in the modulation of cell motility and angiogenesis (Wei et al 2014 ). Although the pleiotropic effects exerted by CD44 in exosome biogenesis and function in cancer and chronic kidney disease have been investigated (Chen et al 2022 ; Kelemen et al 2022 ; Shen et al 2021 ), the role of CD44 in exosomes under MI injury is still poorly understood. Given that exosomes triggering cell-to-cell communication turned out to be a major mechanism underlying the pathophysiology of MI, we proposed that the cell adhesion molecule CD44 may function as a regulator of the biogenesis of exosomes as well as the functional adjustment of exosomes in myocardial ischemic angiogenesis.…”