Sestrin2 is identified as a stress-induced protein and could functionate in many aspects. In our study, we investigated the latent impact of Sestrin2 on podocyte injury and its molecular mechanism in vivo and in vitro in diabetic kidney disease (DKD). Sestrin2 was low-expressed in renal biopsies from individuals with DKD, the glomeruli from diabetic mice, and mouse podocytes exposed to high glucose (HG). Sestrin2 overexpression ameliorated HG-induced phenotypic alterations, apoptosis, and oxidative stress in conditionally immortalized mouse podocytes and modulated the activity of Thrombospondin-1 (TSP-1)/transforming growth factor (TGF-β1)/Smad3 pathway in podocytes. Moreover, TSP-1 inhibitor LSKL or TGF-β blocker Pirfenidone arrested podocyte injury induced by HG. Streptozotocin (STZ) was employed to render equivalent diabetes in B6-TgN (CMV-Sestrin2) (TgN) and wild-type (WT) control mice. Sestrin2 alleviated increased levels of 24‐h urinary protein, blood urea nitrogen, serum creatinine and triglyceride, and urine 8-OHdG in diabetic mice. Podocyte phenotypic alterations, increased expression of apoptosis-associated proteins and podocyte loss were observed in WT but not in diabetic TgN mice, as well as oxidative stress. Additionally, TSP-1/TGF-β1/Smad3 signaling pathway was also suppressed in glomeruli of diabetic TgN mice. Thus, Sestrin2 mitigates podocyte injury in DKD via orchestrating TSP-1/TGF-β1/Smad3 pathway, underlining Sestrin2 as a promising therapeutic target for DKD.
Background:Hypertension is a highly prevalent disorder. A nomogram to estimate the risk of hypertension in Chinese individuals is not available.Methods:6201 subjects were enrolled in the study and randomly divided into training set and validation set at a ratio of 2:1. The LASSO regression technique was used to select the optimal predictive features, and multivariate logistic regression to construct the nomograms. The performance of the nomograms was assessed and validated by AUC, C-index, calibration curves, DCA, clinical impact curves, NRI, and IDI.Results:The nomogram140/90 was developed with the parameters of family history of hypertension, age, SBP, DBP, BMI, MCHC, MPV, TBIL, and TG. AUCs of nomogram140/90 were 0.750 in the training set and 0.772 in the validation set. C-index of nomogram140/90 were 0.750 in the training set and 0.772 in the validation set. The nomogram130/80 was developed with the parameters of family history of hypertension, age, SBP, DBP, RDWSD, and TBIL. AUCs of nomogram130/80 were 0.705 in the training set and 0.697 in the validation set. C-index of nomogram130/80 were 0.705 in the training set and 0.697 in the validation set. Both nomograms demonstrated favorable clinical consistency. NRI and IDI showed that the nomogram140/90 exhibited superior performance than the nomogram130/80. Therefore, the web-based calculator of nomogram140/90 was built online.Conclusions:We have constructed a nomogram that can be effectively used in the preliminary and in-depth risk prediction of hypertension in a Chinese population based on a 10-year retrospective cohort study.Funding:This study was supported by the Hebei Science and Technology Department Program (no. H2018206110).
Renal fibrosis is characterized by glomerulosclerosis and tubulointerstitial fibrosis in diabetic nephropathy (DN). We aimed to evaluate the effects of PP2 on renal fibrosis of DN. GSE33744 and GSE86300 were downloaded from the GEO database. Firstly, 839 DEGs were identified between nondiabetic and diabetic mice renal glomerular samples. COX-2 was selected to assess the effects of PP2 on renal glomerulosclerosis. In db/db mice, PP2 decreased the expression of COX-2, phosphorylated p65, and fibrotic proteins, accompanied with attenuated renal glomerulosclerosis. In cultured glomerular mesangial cells, high glucose- (HG-) induced p65 phosphorylation and COX-2 expression were attenuated by PP2 or NF-κB inhibitor PDTC. PP2, PDTC, or COX-2 inhibitor NS-398 ameliorated abnormal proliferation and expression of fibrotic proteins induced by HG. Secondly, 238 DEGs were identified between nondiabetic and diabetic mice renal cortex samples. UCP2 was selected to assess the effects of PP2 on renal tubulointerstitial fibrosis. In db/db mice, PP2 decreased the expression of PPARγ and UCP2, accompanied with attenuated renal tubulointerstitial fibrosis and EMT. In cultured proximal tubular cells, HG-induced PPARγ and UCP2 expression was inhibited by PP2 or PPARγ antagonist GW9662. PP2, GW9662, or UCP2 shRNA ameliorated HG-induced EMT. These results indicated that PP2 ameliorated renal fibrosis in diabetic mice.
Background The primary pathophysiology of diabetic kidney disease (DKD) is tubulointerstitial fibrosis (TIF), and an essential contributing element is excessive extracellular matrix deposition. Irisin is a polypeptide formed by splitting fibronectin type III domain containing 5 (FNDC5), which participates in a number of physiological and pathological processes. Methods The purpose of this article is to examine irisin’s function in DKD and analyze both its in vitro and in vivo effects. The Gene Expression Omnibus (GEO) database was used to download GSE30122, GSE104954, and GSE99325. Analysis of renal tubule samples from nondiabetic and diabetic mice identified 94 differentially expressed genes (DEGs). The transforming growth factor beta receptor 2 (TGFBR2), irisin, and TGF-β1 were utilized as DEGs to examine the impact of irisin on TIF in diabetic kidney tissue, according to the datasets retrieved from the GEO database and Nephroseq database. Additionally, the therapeutic impact of irisin was also examined using Western blot, RT-qPCR, immunofluorescence, immunohistochemistry, and kits for detecting mouse biochemical indices. Results In vitro, the findings demonstrated that irisin not only down-regulated the expression of Smad4 and β-catenin but also reduced the expression of proteins linked to fibrosis, the epithelial-mesenchymal transition (EMT), and mitochondrial dysfunction in HK-2 cells maintained in high glucose (HG) environment. In vivo, overexpressed FNDC5 plasmid was injected into diabetic mice to enhance its expression. Our studies found that overexpressed FNDC5 plasmid not only reversed the biochemical parameters and renal morphological characteristics of diabetic mice but also alleviated EMT and TIF by inhibiting Smad4/β-catenin signaling pathway. Conclusion The above experimental results revealed that irisin could reduce TIF in diabetic mice via regulating the Smad4/β-catenin pathway.
Background: Renal fibrosis is considered the pathway from almost all chronic kidney diseases (CKD) to end-stage renal diseases. The unilateral ureteral obstruction (UUO) model is a well-established experimental animal model to simulate renal fibrosis associated with obstructive nephropathy in an accelerated manner. In this study, in order to understand the development trends of research on UUO-induced renal fibrosis between 2005 and 2022 and predict prospects, we conducted a comprehensive bibliometric and visualized study using Web of Science (WoS). Methods: The articles regarding UUO-induced renal fibrosis were culled from the “Core Collection” of the WoS database. VOSviewer software and the R-Bibliometrix Package were used in visual analysis of countries/regions, journals, authors, keywords, institutions, and highly cited articles in this field. Results: The number of articles regarding UUO-induced renal fibrosis has obviously increased annually. China had the largest number of publications in this field. The most frequently used keywords were “inflammation,” “transforming growth factor-beta1,” “oxigative stress,” “smad3,” “beta-catenin,” and “autophagy.” Am J Physiol-Renal was the leading journal. The most highly influential documents were published by Higgins DF and his colleagues, with 46 local citations and 749 global citations. The leading institution was Nanjing Medical University. Furthermore, Zhang Y. was the author who contributed most to this field. Conclusion: Our results suggest that the molecular mechanism of UUO-induced renal fibrosis remains a research hot topic, especially on the inflammatory response and oxidative stress, and international cooperation is expected to expand and deepen in the future.
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