podocyte injury
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2022 ◽  
Vol 12 ◽  
Author(s):  
Chunhong Wang ◽  
Jiafeng Liu ◽  
Xiaoyao Zhang ◽  
Qiyan Chen ◽  
Xiaoyan Bai ◽  
...  

Podocyte injury and proteinuria are the most common features of glomerular disease, which is the leading cause of end-stage renal failure. Hyperactivated Wnt/β-catenin signaling is closely associated with podocyte injury, but the underlying mechanisms are incompletely understood. Here we show that miRNA-671-5p (miR-671-5p) plays a crucial role in mediating β-catenin-triggered podocyte injury by targeting Wilms tumor 1 (WT1). Microarray-based expression profiling revealed that miR-671-5p was the most upregulated miRNA in podocytes after β-catenin activation. MiR-671-5p was colocalized with β-catenin in the glomeruli of proteinuric CKD in vivo. Bioinformatics analyses and luciferase reporter assays confirmed that miR-671-5p targeted WT1 mRNA. Overexpression of miR-671-5p mimics inhibited WT1 and impaired podocyte integrity, whereas miR-671-5p antagomir preserved the expression of WT1 and other podocyte-specific proteins under basal conditions or after β-catenin activation. In mouse remnant kidney model, overexpression of miR-671-5p aggravated podocyte injury, worsened kidney dysfunction and exacerbated renal fibrosis after 5/6 nephrectomy. In contrast, miR-671-5p antagomir alleviated podocyte injury and attenuated proteinuria and renal fibrotic lesions after glomerular injury in vivo. These studies underscore a pivotal role of miR-671-5p in mediating WT1 depletion and podocyte injury induced by β-catenin. Targeting miR-671-5p may serve as a new approach to prevent podocyte injury and proteinuria in proteinuric CKD.


2022 ◽  
Vol 12 ◽  
Author(s):  
Zongwei Zhang ◽  
Wei Liang ◽  
Qiang Luo ◽  
Hongtu Hu ◽  
Keju Yang ◽  
...  

BackgroundGlycolysis dysfunction is an important pathogenesis of podocyte injury in diabetic kidney disease (DKD). Foot process fusion of podocytes and increased albuminuria are markers of early DKD. Moreover, cytoskeletal remodeling has been found to be involved in the foot process fusion of podocytes. However, the connections between cytoskeletal remodeling and alterations of glycolysis in podocytes in DKD have not been clarified.MethodsmRNA sequencing of glomeruli obtained from db/db and db/m mice with albuminuria was performed to analyze the expression profiling of genes in glucose metabolism. Expressions of phosphofructokinase platelet type (PFKP) in the glomeruli of DKD patients were detected. Clotrimazole (CTZ) was used to explore the renal effects of PFKP inhibition in diabetic mice. Using Pfkp siRNA or recombinant plasmid to manipulate PFKP expression, the effects of PFKP on high glucose (HG) induced podocyte damage were assessed in vitro. The levels of fructose-1,6-bisphosphate (FBP) were measured. Targeted metabolomics was performed to observe the alterations of the metabolites in glucose metabolism after HG stimulation. Furthermore, aldolase type b (Aldob) siRNA or recombinant plasmid were applied to evaluate the influence of FBP level alteration on podocytes. FBP was directly added to podocyte culture media. Db/db mice were treated with FBP to investigate its effects on their kidney.ResultsmRNA sequencing showed that glycolysis enzyme genes were altered, characterized by upregulation of upstream genes (Hk1, and Pfkp) and down-regulation of downstream genes of glycolysis (Pkm, and Ldha). Moreover, the expression of PFKP was increased in glomeruli of DKD patients. The CTZ group presented more severe renal damage. In vitro, the Pfkp siRNA group and ALDOB overexpression group showed much more induced cytoskeletal remodeling in podocytes, while overexpression of PFKP and suppression of ALDOB in vitro rescued podocytes from cytoskeletal remodeling through regulation of FBP levels and inhibition of the RhoA/ROCK1 pathway. Furthermore, targeted metabolomics showed FBP level was significantly increased in HG group compared with the control group. Exogenous FBP addition reduced podocyte cytoskeletal remodeling and renal damage of db/db mice.ConclusionsThese findings provide evidence that PFKP may be a potential target for podocyte injury in DN and provide a rationale for applying podocyte glycolysis enhancing agents in patients with DKD.


2022 ◽  
pp. 1-13
Author(s):  
Aoyang Guo ◽  
Yadi Sun ◽  
Xiaona Xu ◽  
Qian Xing

2022 ◽  
Author(s):  
Musleeha Chesor ◽  
Jack Tuffin ◽  
Carl May ◽  
Irene Ghobrial ◽  
Melissa Little ◽  
...  

Abstract Recurrence of steroid-resistant nephrotic syndrome (SRNS) is thought to be due to an unknown “circulating factor”, the identity of which has so far remained elusive. Our previous work suggests a signaling role for protease-activated receptor-1 (PAR-1), leading to impaired podocyte function. Here, we show that relapse nephrotic plasma (NP), but not paired remission plasma, induced a pro-fibrotic response. This change was inhibited by PAR-1 inhibitors, but not by TGF-β1 inhibition. Four PAR-1 inhibitors demonstrated distinct antagonistic properties. The phosphorylation of VASP and JNK in a 3D spheroid model (GlomSpheres) and kidney organoids corroborated the finding from a 2D ciPods model. Functionally, relapse NP induced podocyte motility, and podocyte loss from spheroids both of which were also selectively rescued by PAR-1 inhibitors. Also, it induced the loss of podocyte-specific markers in kidney organoids. We propose that the circulating factor acts as a pro-fibrotic effector by activating PAR-1, leading to increased podocyte injury.


Author(s):  
Haiying Wang ◽  
Ran Zhang ◽  
Xinjie Wu ◽  
Yafen Chen ◽  
Wei Ji ◽  
...  

Diabetic nephropathy (DN) is a serious kidney-related complication of both type 1 and type 2 diabetes mellitus (T1DM, T2DM) and the second major cause of end-stage kidney disease. DN can lead to hypertension, edema, and proteinuria. In some cases, DN can even progress to kidney failure, a life-threatening condition. The precise etiology and pathogenesis of DN remain unknown, although multiple factors are believed to be involved. The main pathological manifestations of DN include mesangial expansion, thickening of the glomerular basement membrane, and podocyte injury. Eventually, these pathological manifestations will lead to glomerulosclerosis, thus affecting renal function. There is an urgent need to develop new strategies for the prevention and treatment of DN. Existing evidence shows that the Wnt signaling cascade plays a key role in regulating the development of DN. Previous studies focused on the role of the Wnt canonical signaling pathway in DN. Subsequently, accumulated evidence on the mechanism of the Wnt non-canonical signaling indicated that Wnt/Ca2+ and Wnt/PCP also have essential roles in the progression of DN. In this review, we summarize the specific mechanisms of Wnt signaling in the occurrence and development of DN in podocyte injury, mesangial cell injury, and renal fibrosis. Also, to elucidate the significance of the Wnt canonical pathway in the process of DN, we uncovered evidence supporting that both Wnt/PCP and Wnt/Ca2+ signaling are critical for DN development.


2022 ◽  
Author(s):  
Yani YU ◽  
Hui DONG ◽  
Yue ZHANG ◽  
Jingyi SUN ◽  
Baoshuang LI ◽  
...  

Abstract Hepatitis B virus (HBV) and its related protein, HBV X (HBx), play an important role in podocyte injury in HBV-associated glomerulonephritis (HBV-GN). MiR-223 is expressed in several diseases, including HBV-associated disease, while nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome plays a major role in pyroptosis. This study aims to determine the potential function and related mechanism of miR-223 in HBx-induced podocyte pyroptosis. We observed that the results of polymerase chain reaction indicated that miR-223 was downregulated in HBx-transfected podocytes. Transfection of miR-223 mimic eliminated the expression of NLRP3 inflammasome and its related cytokines released by NLRP3 overexpression. Moreover, the transfection of HBx and NLRP3-overexpressing plasmids increased the expression of pyroptosis-related proteins especially in the presence of miR-223 inhibitors. In conclusion, miR-223 downregulation plays an important role in HBx-induced podocyte pyroptosis by targeting the NLRP3 inflammasome, suggesting that miR-223 is a potential therapeutic target for alleviating HBV-GN inflammation.


Theranostics ◽  
2022 ◽  
Vol 12 (2) ◽  
pp. 767-781
Author(s):  
Hongyan Mo ◽  
Qian Ren ◽  
Dongyan Song ◽  
Bo Xu ◽  
Dong Zhou ◽  
...  
Keyword(s):  

Author(s):  
Ling Jiang ◽  
Xue-qi Liu ◽  
Xue-ru Hu ◽  
Li Gao ◽  
Han-xu Zeng ◽  
...  

2022 ◽  
Vol 18 (1) ◽  
pp. 96-111
Author(s):  
Jian Lu ◽  
Pei Pei Chen ◽  
Jia Xiu Zhang ◽  
Xue Qi Li ◽  
Gui Hua Wang ◽  
...  

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