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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) and renal fibrosis, suggesting intimate communication between the two diseases. 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 tubular cell-derived exosomes were aroused by β-catenin in kidney fibrogenesis. Osteopontin (OPN), especially its N-terminal fragments (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 secreted by exosome 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE193282 | GEO | 2022/12/20

REPOSITORIES: GEO

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

Project description:Tubular injury and peripheral fibroblast activation are the hallmarks of chronic kidney disease (CKD) and renal fibrosis, suggesting intimate communication between the two diseases. 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 tubular cell-derived exosomes were aroused by β-catenin in kidney fibrogenesis. Osteopontin (OPN), especially its N-terminal fragments (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 secreted by exosome 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.

2022-05-20 | PXD030696 | Pride

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Exosomes derived from TREM-2 knocked-out macrophages alleviated renal fibrosis via HSPa1b/AKT pathway

Project description:Macrophages are recognized as the vital players in renal fibrosis, with a high degree of heterogeneity and plasticity, and triggering receptor expressed on myeloid cell-2(TREM-2) was highly expressed on macrophages and participated in the progression of tissue fibrosis. However, the mechanism by which TREM-2 mediate the progress of renal fibrosis is still unclear. Our study have found the exosomes derived from TREM-2 deficient (TREM-2-/-) macrophages could suppress the progression of fibrosis, showing a higher matrix metalloproteinase-9 (MMP-9) / tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) ration at protein level in secreted exosomes than exosomes from WT（wild type）macrophages in the fibrotic microenvironment. Besides, renal tubular epithelial cells (TECs) engulfed theses nanoscale vesicles, the expression of collagen I and α-smooth muscle actin (α-SMA) (fibrosis related marker) was obviously decreased. Through the RNA-seq, we found that TREM-2-/- macrophages upregulate the MMP-9/TIMP-1 ratio in its exosomes via HSPa1b/AKT pathway. Furthermore, it’s noteworthy that the renal fibrosis was effectively alleviated in the obstructed kidney from mice received a renal pelvis injection of adeno associated virus (AAV-shTREM-2) containing the sequence of silencing TREM-2. However, VER-155008 (inhibitor of HSPa1b) and Ly294002 (inhibitor of AKT) reversed this effect. Moreover, polyclonal antibodies against TREM-2 also effectively relieved the UUO-induced renal fibrosis. Above all, we have validated that the knocking down TREM-2 expression can inhibit the progression of renal fibrosis through a macrophage exosome-dependent pathway in vitro and vivo. Hence, our finding suggest TREM-2 is potential therapeutic target for CKD.

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

Project description:β-catenin-controlled tubular cell-derived exosomes play a key role in fibroblast activation via the OPN-CD44 axis

| PRJNA795662 | ENA

Development of gene expression profiles in human chronic kidney disease

Project description:A microarray analysis with renal biopsy specimens from CKD patients was conducted in order to identify the responsible genes associated with tubulointerstitial fibrosis and tubular cell injury in CKD. This study showed microarray profiles in total 53 biopsy specimens of CKD patients. In the discovery set, 554 down-regulated and 226 up-regulated signatures were identified. Then, the expressional changes of these genes were examined in the validation set. Gene expression profiles in human chronic kidney disease was explored using renal biopsy specimens. Two independent studies: discovery set and validation set were performed. This dataset is part of the TransQST collection.

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Secretory Leukocyte Peptidase Inhibitor (SLPI) is a Novel Predictor of Tubulointerstitial Injury and Renal Outcome in Patients with Diabetic Nephropathy

Project description:Tubulointerstitial injury plays an important role in diabetic nephropathy (DN) progression; however, no reliable urinary molecule has been used to predict tubulointerstitial injury and renal outcome of DN clinically. In this study, based on tubulointerstitial transcriptome, we identified secretory leukocyte peptidase inhibitor (SLPI) as the molecule associated with renal fibrosis and prognosis of DN. In tubular cells, high glucose could upregulate SLPI, which bound with β-catenin and GSK-3β reciprocally, abolished the interaction between β-catenin and GSK-3β, diminished GSK-3β-regulated β-catenin phosphorylation and the subsequent ubiquitination and degradation, thus led to β-catenin signaling activation and renal fibrosis. Db/db mice injected with adenovirus carrying Slpi-3xflag-GFP (Ad-Slpi-GFP) developed β-catenin signaling activation in the proximal tubule, worse albuminuria and tubulointerstitial fibrosis. Conversely, Slpi knockout (KO) mice with STZ-induced DN developed less albuminuria, tubulointerstitial fibrosis and β-catenin signaling activation. Furthermore, clinical studies showed that urinary SLPI protein level (uSLPI/Cr) had significant correlation with intrarenal SLPI mRNA and interstitial fibrosis. In an independent prospective cohort enrolled 711 patients with biopsy proven DN, uSLPI/Cr level was significantly associated with eGFR slope and improved the prediction value of renal outcome. Together, our study identified SLPI as a novel critical regulator for the progression of tubulointerstitial injury, which may be used as an independent risk predictor of DN progression.

2022-08-03 | GSE158230 | GEO

RNA-seq of TGF-beta1-induced NRK-52E cells after treatment with 2D- and 3D-EVs

Project description:Renal tubular epithelial cells are the main cells affected in the process of renal fibrosis, and it has been shown that mesenchymal stem cell-derived exosomes can treat renal fibrosis, and then the traditional 2D-EVs production method is inefficient. We efficiently extracted 3D-EVs by coaxial bioprinting, but the mechanism of 3D-EVs for treating renal fibrosis is not yet known. Therefore, we used TGF-beta1 to induce a renal fibrosis phenotype in NRK-52E cells and took 2D- and 3D-EVs for treatment in order to explore the possible differential molecular mechanisms of 2D- and 3D-EVs for renal fibrosis. This approach facilitates the discovery of new mechanisms for exosomes to treat renal fibrosis.

2024-12-18 | GSE281863 | GEO

Tubular insulin-induced gene 1 deficiency promotes NAD+ consumption and exacerbates kidney fibrosis

Project description:<p>Profibrotic proximal tubular (PT) were identified as a unique phenotype of PTCs in renal fibrosis by single-cell RNA sequencing (scRNA-seq). Controlling the process of renal fibrosis requires understanding how to manage the S1 subset's branch to the S3 subset rather than to the profibrotic PT subset. Insulin-induced gene 1 (Insig1) is one of the branch-dependent genes involved in controlling this process, although its role in renal fibrosis is unknown. Here, we discovered that tubular Insig1 deficiency, rather than fibroblast Insig1 deficiency, play a detrimental role in the pathogenesis of renal fibrosis in vivo and in vitro. Overexpression of Insig1 profoundly inhibited renal fibrosis. Mechanistically, Insig1 deletion in PTCs boosted SREBP1 nuclear localization, increasing Aldh1a1 transcriptional activity, causing excessive NAD+ consumption and ER enlargement, as well as accelerating renal fibrosis. We also identified nicardipine as a selective inhibitor of Aldh1a1, which could restore NAD+ and maintain ER homeostasis, as well as improve renal fibrosis. Together, our findings support tubular Insig1 as a new therapeutic target for chronic kidney disease (CKD).</p>

1970-01-01 | MTBLS9985 | MetaboLights

Development of gene expression profiles in human chronic kidney disease

2015-08-16 | GSE66494 | GEO

Immunohistochemical Investigation for Renal Tubules in Adaptive and Maladaptive Repair Process after Renal Tubular Injury in the Kidney of Rats

Project description:Acute kidney injury (AKI) have been thought to be reversible condition, however, emerging evidence demonstrated association between AKI and subsequent development of irreversible fibrosis and chronic kidney disease. In the present study, since recovery of AKI depends on renal tubular regeneration, factors expressing in renal tubules in adaptive or maladaptive repair process were investigated to predict reversibility of kidney injury. In the kidney of female F344 rats subjected to ischemia/reperfusion (I/R), regenerative tubules and dilated tubules were observed at 3 and 7 days after I/R. In fibrotic areas of the kidney of male SD rats subjected to I/R, renal tubules were dilated or atrophied. From microarray data of regenerative tubules, survivin, sex-determining region Y (SRY)-box 9 (SOX9), and CD44 were extracted as factors possibly relating to tubular regeneration or fibrosis. Immunohistochmical analysis demonstrated that survivin and SOX9 expressed in regenerative tubules, while SOX9 also expressed in renal tubules in fibrotic area, indicating that survivin and SOX9 contribute renal tubular regeneration, but sustained SOX9 expression may lead fibrosis. CD44 expressed in dilated tubules at day 3 and 7, and tubules in fibrotic area, suggesting that CD44 expressed in maladaptive tubules. These information will be helpful to consider reversibility of kidney injury.

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