Fibrosis In Diabetic Nephropathy Research Articles

Human umbilical cord mesenchymal stem cell-derived exosomes ameliorate renal fibrosis in diabetic nephropathy by targeting Hedgehog/SMO signaling.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease globally. Currently, there are no effective drugs for the treatment of DN. Although several studies have reported the therapeutic potential of mesenchymal stem cells, the underlying mechanisms remain largely unknown. Here, we report that both human umbilical cord MSCs (UC-MSCs) and UC-MSC-derived exosomes (UC-MSC-exo) attenuate kidney damage, and inhibit epithelial-mesenchymal transition (EMT) and renal fibrosis in streptozotocin-induced DN rats. Strikingly, the Hedgehog receptor, smoothened (SMO), was significantly upregulated in the kidney tissues of DN patients and rats, and positively correlated with EMT and renal fibrosis. UC-MSC and UC-MSC-exo treatment resulted in decrease of SMO expression. Invitro co-culture experiments revealed that UC-MSC-exo reduced EMT of tubular epithelial cells through inhibiting Hedgehog/SMO pathway. Collectively, UC-MSCs inhibit EMT and renal fibrosis by delivering exosomes and targeting Hedgehog/SMO signaling, suggesting that UC-MSCs and their exosomes are novel anti-fibrotic therapeutics for treating DN.

Icariin alleviates diabetic renal interstitial fibrosis aggravation by inhibiting miR-320a-3p targeting BMP6

Diabetic nephropathy is a common complication of diabetes, accumulating evidence underscores the pivotal role of tubulointerstitial fibrosis in the progression of diabetic nephropathy. However, the underlying mechanisms remain incompletely understood. Although the mechanisms in diabetic nephropathy fibrosis have been the focus of many studies, only limited information is currently available concerning microRNA regulation in tubulointerstitial fibrosis. In this study, we aimed to investigate the roles of miR-320a-3p and bone morphogenetic protein-6 (BMP6) in tubulointerstitial fibrosis. After inducing fibrosis with high glucose in HK-2 cells, we found that miR-320a-3p is significantly up-regulated, whereas BMP6 is markedly down-regulated. These changes suggest close link between miR-320a-3p and BMP6 in tubulointerstitial fibrosis. To elucidate this phenomenon, miR-320a-3p mimic, inhibitor and siBMP6 were employed. We observed in miR-320a-3p mimic group the fibrosis marker include alpha smooth muscle actin and type I collagen was significantly up-regulated, whereas BMP6 exhibited the opposite trend. Additionally, we found icariin could alleviate tubulointerstitial fibrosis by downregulation the miR-320a-3p expression. In conclusion, miR-320a-3p promotes tubulointerstitial fibrosis during the development of DN by suppressing BMP signal pathway activity via inhibiting BMP6 expression. Suggesting that miR-320a-3p represents a potential therapeutic target for tubulointerstitial fibrosis induced by diabetic nephropathy.

Pericyte activation accompanied by peritubular capillaries dysfunction and pericyte-to-myofibroblast transition is associated with renal fibrosis in diabetic nephropathy.

Tubulointerstitial renal fibrosis is an essential feature of diabetic nephropathy (DN). Pericytes play a critical role in microvascular diseases and renal fibrogenesis. However, the role of pericytes in DN remains unclear. Herein, we aimed to explore the properties and possible mechanisms of pericytes in renal fibrosis in DN. We used multiplex immunofluorescence staining to evaluate the location and expression of activated pericytes and to assess capillary dilation and interstitial fibrosis in the kidneys of db/db mice. Pericytes were co-stained for alpha-smooth muscle actin (α-SMA) to determine which ones differentiate into myofibroblasts in db/db mice. Expression of CD34 and platelet-derived growth factor receptor beta (PDGFR-β) was assessed in kidney tissue from patients with DN by immunohistochemical staining. We found that cell staining for nerve/glial antigen 2 (NG2)+ and PDGFR-β+ was greater in the kidneys of db/db mice than in those of db/m mice. There was impaired pericyte coverage of blood vessels and capillary dilation in the renal interstitium. These changes were accompanied by increased collagen I staining and an increase in the number of pericytes with profibrotic phenotypes, as identified by increased NG2+/PDGFR-β+/α-SMA+ and decreased NG2+/PDGFR-β+/α-SMA- staining. In DN patients, expression of PDGFR-β was stronger and there was loss of CD34 compared with the findings in control patients with minor glomerular lesions. In this study, we demonstrated that pericyte activation accompanied by peritubular capillary dysfunction and pericytemyofibroblast transition is associated with renal fibrosis in DN.

Jin-Gui-Shen-Qi Wan alleviates fibrosis in mouse diabetic nephropathy via MHC class II

Ethnopharmacological relevanceJin-Gui-Shen-Qi Wan (JGSQW) is a traditional Chinese medicine formula that has been traditionally used to alleviate urinary system ailments such as frequent urination and polyuria. Clinical studies have indicated that when combined with hypoglycaemic drugs, JGSQW exhibits a synergistic effect and can improve diabetic nephropathy (DN), yet its underlying mechanism and targets remain unclear. Aim of the studyThis study aims to investigate the therapeutic efficacy of JGSQW and its underlying mechanisms using a DN db/db mouse model. Materials and methodsUltrahigh-performance liquid chromatography coupled with mass spectrometry was utilized to analyse the primary active compounds, blood levels, and pharmacokinetics of JGSQW. Additionally, the therapeutic effects of JGSQW and metformin on blood glucose levels, lipid levels, renal function, and renal pathology in diabetic nephropathy mice were investigated using a db/db mouse model. Proteomic analysis was carried out to identify the primary target of JGSQW in treating DN. The mechanism of action was verified by western blotting, immunohistochemistry, and immunofluorescence. Then, molecular docking and molecular dynamics, transfection, drug affinity responsive target stability (DARTS) assay and cell thermal migration assay (CETSA) further validated the targeted binding effect. ResultsJGSQW combined with metformin significantly improved the blood glucose levels, blood lipids, renal function, and renal pathology of DN mice. JGSQW mainly exerted its therapeutic effect on DN by targeting major histocompatibility complex class II (MHC class II) molecules. Immunohistochemistry results showed that JGSQW inhibited the expression of collagen I, fibronectin, and alpha smooth muscle actin (α-SMA) expression. Immunofluorescence and Western blot results showed that JGSQW inhibited the expression of H2-Ab1 and H2-Aa, which are MHC class II molecules, thereby suppressing CD4+ T-cell infiltration and improving diabetic kidney fibrosis. The binding ability of paeoniflorin to H2-Aa was predicted and verified by molecular, DARTS, and CETSA assays. Treatment with 80 μM paeoniflorin effectively alleviated high glucose-induced injury in the MPC-5 injury model. H2-Aa was overexpressed at this model concentration, and Western blotting further confirmed that paeoniflorin reduced glomerular podocyte fibrosis by regulating H2-Aa. ConclusionsJGSQW combined with metformin may have a synergistic effect to alleviates renal fibrosis in diabetic nephropathy by downregulating immune complex MHC class II molecules and attenuating the antigen presentation effect of MHC class II on CD4.

Cordyceps cicadae polysaccharides attenuate diabetic nephropathy via the miR-30a-3p/TRIM16 axis.

The molecular mechanism of the protective effect of Cordyceps cicadae polysaccharides (CCPs) on renal tubulointerstitial fibrosis in diabetic nephropathy (DN) is still unclear. This study aims to further understand the molecular mechanisms behind the therapeutic benefits of CCP on diabetic nephropathy. Mice were randomly assigned into six groups (n = 8). Cordyceps cicadae polysaccharide dissolved in 5% dimethyl sulfoxide was administered by gavage for 12 consecutive weeks. The CCP doses were divided into low, medium, and high, 75, 150, and 300 mg/kg/day, respectively. The efficacy of CCP was determined by assessing the renal function and histological alterations in diabetic db/db mice. The degree of glomerular mesangial dilatation and sclerosis was evaluated using semiquantitative markers. Cell viability, apoptosis, epithelial-mesenchymal transition (EMT), inflammation, oxidative stress, and mitochondrial reactive oxygen species (ROS) in high glucose (HG)-cultured MPC5 podocytes were determined. The interaction of miR-30a-3p and tripartite motif-containing protein 16 (TRIM16) was examined by luciferase reporter assay. Western blotting, reverse transcription-polymerase chain reaction, and immunofluorescence were used to analyze gene and protein expressions. The in vivo findings illustrated that CCP may protect mice with type 2 diabetes from inflammation and oxidative damage (P < 0.05). Furthermore, CCP has a therapeutic value in protecting renal function and morphology in diabetic nephropathy by reversing podocyte EMT. The in vitro results indicated that CCP dose-dependently inhibited HG-induced apoptosis, EMT, inflammation, oxidative stress, and mitochondrial ROS levels in MPC5 podocytes (P < 0.05). Luciferase reporter assay confirmed the interaction between miR-30a-3p and TRIM16 in MPC5 podocytes cultured in high glucose (P < 0.05). The protective effect of CCP on HG-induced MPC5 can be achieved by miR-30a-3p/TRIM16 axis.

Macrophages release IL11-containing filopodial tip vesicles and contribute to renal interstitial inflammation

Macrophage filopodia, which are dynamic nanotube-like protrusions, have mainly been studied in the context of pathogen clearance. The mechanisms by which they facilitate intercellular communication and mediate tissue inflammation remain poorly understood. Here, we show that macrophage filopodia produce a unique membrane structure called “filopodial tip vesicle” (FTV) that originate from the tip of macrophages filopodia. Filopodia tip-derived particles contain numerous internal-vesicles and function as cargo storage depots via nanotubular transport. Functional studies indicate that the shedding of FTV from filopodia tip allows the delivery of many molecular signalling molecules to fibroblasts. We observed that FTV derived from M1 macrophages and high glucose (HG)-stimulated macrophages (HG/M1-ftv) exhibit an enrichment of the chemokine IL11, which is critical for fibroblast transdifferentiation. HG/M1-ftv induce renal interstitial fibrosis in diabetic mice, while FTV inhibition or targeting FTV IL11- alleviates renal interstitial fibrosis, suggesting that the HG/M1-ftvIL11 pathway may be a novel mechanism underlying renal fibrosis in diabetic nephropathy. Collectively, FTV release could represent a novel function by which filopodia contribute to cell biological processes, and FTV is potentially associated with macrophage filopodia-related fibrotic diseases.8XMabVtTRQ4kBojsCRSFmYVideo

Periostin deficiency attenuates kidney fibrosis in diabetic nephropathy by improving pancreatic β-cell dysfunction and reducing kidney EMT

Diabetic nephropathy (DN) is associated with kidney fibrosis. A previous study revealed that periostin (POSTN) contributes to kidney fibrosis. This study examined the role of POSTN in DN. The urinary concentrations of POSTN and TNC increased according to the severity of DN in human samples. Streptozotocin (STZ) was administered after unilateral nephrectomy (UNXSTZ) to induce DN in wild-type and Postn-null mice. Four experimental groups were generated: wild-typeham (WT Sham), wild-type UNXSTZ (WT STZ), Postn-null Sham (KO Sham), and Postn-null UNXSTZ (KO STZ). After 20 weeks, the KO STZ group had lower levels of urine albumin excretion, glomerular sclerosis, and interstitial fibrosis than those of the WT STZ group. Additionally, the KO STZ group had lower expression of fibrosis markers, including TNC. The KO STZ group showed better glucose regulation than the WT STZ model. Furthermore, the KO STZ group exhibited significantly preserved pancreatic islet integrity and insulin expression. HK-2 cells were used to observe the aggravation of fibrosis caused by POSTN under TGF-β conditions. We stimulated INS-1 cells with streptozotocin and evaluated the viability of these cells. The anti-POSTN antibody treatment of INS-1 cells with streptozotocin resulted in higher cell viability than that with treatment with streptozotocin alone. The absence of POSTN in DN contributes to renal fibrosis alleviation by improving pancreatic β-cell function. Additionally, there is an association between POSTN and TNC.

LINC01232 targeting miR-1250-3p/MSH2 axis attenuates mesangial cell proliferation and fibrosis in diabetic nephropathy.

The significance of long non-coding RNA (ncRNAs) in the initiation and progression of diabetic nephropathy (DN) has attracted much interest. The purpose of this work was to ascertain the role of LINC01232 in cell models and animal models of DN. C57BL/6J mice were administered with streptozotocin (STZ) to develop animal models of DN, and mouse glomerular mesangial cells (MCs) were exposed to high glucose (HG) to establish cell models of DN. Expression levels of LINC01232, miR-1250-3p and MSH2 were identified by quantitative real-time PCR (qPCR) or western blotting. Fibrosis-related proteins were quantified by western blotting. MC proliferative capacity was checked by EdU assay. DN progression and fibrosis level in animal models were assessed by hematoxylin and eosin (HE) and Masson staining. The potential binding sites between miR-1250-3p and LINC01232 or MSH2 were examined by dual-luciferase reporter assay. LINC01232 expression was heightened in kidney tissues of DN patients. Its overexpression in HG-treated MCs alleviated MC proliferation and fibrosis. Overexpression of LINC01232 alleviated the pathological state of glomerular hypertrophy, MC hyperplasia, basement membrane thickening, and fibrosis in the DN models. LINC01232 bound to miR-1250-3p and competed for miR-1250-3p binding sites with MSH2. LINC01232 overexpression decoyed miR-1250-3p to increase MSH2 expression, and MSH2 depletion restored LINC01232 overexpression-inhibited MC proliferation and fibrosis. LINC01232 alleviated the mesangial cell proliferation and fibrosis in the progression of DN by targeting miR-1250-3p/MSH2 pathway.

Promising therapeutic mechanism for Chinese herbal medicine in ameliorating renal fibrosis in diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most serious chronic microvascular abnormalities of diabetes mellitus and the major cause of uremia. Accumulating evidence has confirmed that fibrosis is a significant pathological feature that contributes to the development of chronic kidney disease in DN. However, the exact mechanism of renal fibrosis in DN is still unclear, which greatly hinders the treatment of DN. Chinese herbal medicine (CHM) has shown efficacy and safety in ameliorating inflammation and albuminuria in diabetic patients. In this review, we outline the underlying mechanisms of renal fibrosis in DN, including oxidative stress (OS) generation and OS-elicited ASK1-p38/JNK activation. Also, we briefly summarize the current status of CHM treating DN by improving renal fibrosis. The treatment of DN by inhibiting ASK1 activation to alleviate renal fibrosis in DN with CHM will promote the discovery of novel therapeutic targets for DN and provide a beneficial therapeutic method for DN.

LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424.

Study has demonstrated the abnormal expression and role of lncRNA CASC15 in diabetes patients with chronic renal failure. However, its role in diabetes nephropathy (DN) is still unclear. This study aimed to investigate the potential mechanism and role of lncRNA CASC15 in DN. The relationship between miR-424 and CASC15/SP-A was predicted by Starbase software and verified by luciferase reporter assay. HK-2 cells were treated with 25 mM glucose (HG) for 24 h to establish DN cell model. MTT and flow cytometry analysis were carried out to test cell proliferation and apoptosis. Epithelial-to-mesenchymal transition (EMT) markers were analyzed by RT-qPCR and western blot assay. We proved that CASC15 could interact with miR-424, and SP-A was a target of miR-424. HG-treatment significantly enhanced lncRNA CASC15 level and decreased miR-424 level in HK-2 cells. LncRNA CASC15-siRNA significantly improved cell viability, repressed apoptosis, promoted E-cadherin expression, and inhibited N-cadherin expression in HG-treated HK-2 cells, and these effects were reversed by miR-424 inhibitor. SP-A was highly expressed in HG-treated HK-2 cells. The biological effects of miR-424 mimic on HG-treated HK-2 cells were reversed by SP-A-plasmid. In conclusion, lncRNA CASC15 inhibition relieved HG-induced HK-2 cell injury and EMT through miR-424/SP-A axis.

Deciphering the anti-renal fibrosis mechanism of triptolide in diabetic nephropathy by the integrative approach of network pharmacology and experimental verification

• TP inhibited ECM deposition and prevented the occurrence of renal fibrosis in diabetic nephropathy . • TP could alleviate renal fibrosis by regulating the GSK3β/Nrf2/HO-1 pathway. • TP could inhibit the overexpression of NOX4 and the ROS level, and ameliorate proteinuria in db/db mice.

Satellite cell-derived exosome-mediated delivery of microRNA-23a/27a/26a cluster ameliorates renal tubulointerstitial fibrosis in diabetic nephropathy

Objective: Renal tubulointerstitial fibrosis (TIF) is the final convergent pathway of diabetic nephropathy (DN), yet no effective targeted therapies currently can prevent the progression of TIF. Here, as a novel and more effective gene therapy approach, the microRNA (miRNA) clusters provide a method to tackle this issue. Methods: Differentially expressed miRNAs in the serum of DN patients were identified by miRNA sequencing (miRNA-seq). We engineered a kidney targeting exosomes (Exos) vector that contained Lamp2b, an exosomal membrane protein gene fused with rabies virus glycoprotein (RVG) peptide. We transfected this vector into muscle satellite cells and then transduced these cells with adenovirus that expresses miR-23a/27a/26a cluster to manufacture the resultant Exos denoted as RVG-miR-23a/27a/26a-Exos. Db/db mice were injected by tail vein with RVG-miR-23a/27a/26a-Exos and the biodistribution of Exos in db/db mice was imaged by the IVIS. RNA sequencing (RNA-seq) and bioinformatic analysis were performed to explore downstream targets of miRNAs. Results: MiRNA-seq results showed that a total of 23 differentially expressed miRNAs with fold-change &gt;2.0 and p value &lt;0.05 were identified (six downregulated and seventeen upregulated) in serum samples from patients with DN, among which miR-23a, miR-26a, and miR-27a were significantly decreased. Then, it was confirmed that miR-23a, miR-26a and miR-27a expression in the serum of patients with DN were reduced by 47%, 57% and 38%, respectively. Moreover, Pearson's correlation analysis showed that miR-23a, miR-26a and miR-27a had strong negative correlation with TIF and renal function decline. Then, we combined miR-23a, miR-26a and miR-27a as an artificially engineered cluster and successfully engineered RVG-miR-23a/27a/26a cluster loaded exosomes derived from muscle satellite cells, which not only enhanced the stability of miR-23a/27a/26a cluster, but also efficiently delivered more miR-23a/27a/26a cluster homing to injured kidney. More importantly, treatment with RVG-miR-23a/27a/26a-Exos significantly ameliorated tubular injury and TIF in mice with DN. Mechanistically, we showed that miR-23a/27a/26a-Exos could potentiate antifibrotic effects by regulating miRNA cluster-targeting Lpp simultaneously, as well as miR-27a-targeting Zbtb20 and miR-26a-targeting Klhl42, respectively. Conclusions: We established a novel kidney-targeting Exo-based delivery system by manipulating the miRNA-23a/27a/26a cluster to ameliorate TIF in DN effectively, providing a promising therapeutic strategy for DN. This work was supported by the National Natural Science Foundation of China (Nos. 81970664, 82000648, 82070735); the Natural Science Foundation of Jiangsu Province (Nos. BK20211385, BK20200363); the 789 Outstanding Talent Program of SAHNMU (Nos. 789ZYRC202080119, 789ZYRC202090251) and the Science and Technology Development Foundation of Nanjing Medical University (No. NMUB2020049). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Machine learning-based multimodal MRI texture analysis for assessing renal function and fibrosis in diabetic nephropathy: a retrospective study.

Diabetic nephropathy (DN) has become a major public health burden in China. A more stable method is needed to reflect the different stages of renal function impairment. We aimed to determine the possible practicability of machine learning (ML)-based multimodal MRI texture analysis (mMRI-TA) for assessing renal function in DN. For this retrospective study, 70 patients (between 1 January 2013 and 1 January 2020) were included and randomly assigned to the training cohort (n1 = 49) and the testing cohort (n2 = 21). According to the estimated glomerular filtration rate (eGFR), patients were assigned into the normal renal function (normal-RF) group, the non-severe renal function impairment (non-sRI) group, and the severe renal function impairment (sRI) group. Based on the largest coronal image of T2WI, the speeded up robust features (SURF) algorithm was used for texture feature extraction. Analysis of variance (ANOVA) and relief and recursive feature elimination (RFE) were applied to select the important features and then support vector machine (SVM), logistic regression (LR), and random forest (RF) algorithms were used for the model construction. The values of area under the curve (AUC) on receiver operating characteristic (ROC) curve analysis were used to assess their performance. The robust T2WI model was selected to construct a multimodal MRI model by combining the measured BOLD (blood oxygenation level-dependent) and diffusion-weighted imaging (DWI) values. The mMRI-TA model achieved robust and excellent performance in classifying the sRI group, non-sRI group, and normal-RF group, with an AUC of 0.978 (95% confidence interval [CI]: 0.963, 0.993), 0.852 (95% CI: 0.798, 0.902), and 0.972 (95% CI: 0.995, 1.000), respectively, in the training cohort and 0.961 (95% CI: 0.853, 1.000), 0.809 (95% CI: 0.600, 0.980), and 0.850 (95% CI: 0.638, 0.988), respectively, in the testing cohort. The model built from multimodal MRI on DN outperformed other models in assessing renal function and fibrosis. Compared to the single T2WI sequence, mMRI-TA can improve the performance in assessing renal function.

Title: Bioinformatic Identification of Genes Involved in Diabetic Nephropathy Fibrosis and their Clinical Relevance.

Tubulointerstitial fibrosis is an important pathological feature of diabetic nephropathy that is associated with impaired renal function. However, the mechanism by which fibrosis occurs in diabetic nephropathy is unclear. Differentially expressed genes were identified from transcriptome profiles of renal tissue from diabetic patients and unilateral ureteral obstruction mice and intersected to obtain genes that may be involved in diabetic fibrosis. Biological function analysis and protein-protein interaction network analysis were performed. ROC curve and Pearson correlation analysis between hub genes were performed and glomerular filtration rate estimated. Finally, the RNA levels of hub genes were measured using real-time PCR. A total of 283 genes were identified as potentially involved in diabetic nephropathy fibrosis. TYROBP, CTSS, LCP2, LUM and TLR7 were identified as aberrantly expressed hub genes. Immune cell infiltration analysis demonstrated higher numbers of cytotoxic lymphocytes, B lineage cells, monocyte lineage cells, myeloid dendritic cells, neutrophils, and fibroblasts in the diabetic nephropathy group. The areas under ROC curves for TYROBP, CTSS, LCP2, LUM and TLR7 were 0.9167, 0.9583, 0.9917, 0.93333, and 0.9583, respectively (P < 0.001), and their correlation coefficients with estimated glomerular filtration rate were - 0.8332, - 0.752, - 0.7875, - 0.7567, and - 0.7136, respectively (P < 0.001). The RNA levels of TYROBP, CTSS, LUM and TLR7 were upregulated in high-glucose-treated human renal tubular epithelial cells (P < 0.005). Our study identified TYROBP, CTSS, LCP2, LUM and TLR7 as potentially involved in diabetic nephropathy fibrosis. Furthermore, TYROBP, CTSS, LUM and TLR7 may be associated with epithelial-mesenchymal transition of tubular epithelial cells.

Elajik Asit, Diyabetik Böbrek Hasarında TGFβ1/Smad Kaynaklı Böbrek Fibrozisini İnhibe Eder

Aim: Free radical formation increases due to hyperglycemia occurring in the pathogenesis of diabetes mellitus (DM), and as a result, oxidative stress occurs. Hyperglycemia-mediated oxidative stress plays an important role in the pathogenesis of diabetic nephropathy. The antihyperglycemic, antioxidative, anti-apoptotic, and anti-inflammatory effects of ellagic acid (EA) have been demonstrated by many studies. In this study, it was aimed to demonstrate the antifibrotic effect of EA on TGFβ1/Smad signaling in rats with streptozotocin induced diabetic nephropathy. Material and Methods: A total of 24 male Sprague Dawley rats, weighing 200-250 g, were used in this study. The animals were divided into four groups as control, EA, DM, and DM+EA. The kidney tissues were used for histological and immunohistochemical procedures. While the collagen density in kidney tissues was revealed by Masson's trichrome staining, the expression levels of fibrotic markers TGFβ1, p-Smad3, and αSMA were determined by the immunocytochemical method. Results: It was shown that the collagen density in the renal tissue of the DM group increased significantly in the intertubular area, while the collagen density in the EA-treated DM group was statistically significantly decreased. When TGFβ1, p-Smad3, and αSMA immunopositivity in kidney tissue sections of all groups were evaluated, the highest staining intensity was in the DM group, while the intensity of staining was close to the control group in the treatment group. It was observed that αSMA, TGFβ1, and p-Smad3 protein expression were down-regulated with EA treatment. Conclusion: EA reduced fibrosis in diabetic nephropathy by returning profibrotic parameters to normal levels.

A Cyclopentanone Compound Attenuates the Over-Accumulation of Extracellular Matrix and Fibrosis in Diabetic Nephropathy via Downregulating the TGF-β/p38MAPK Axis.

Excessive accumulation of the extracellular matrix (ECM) is a crucial pathological process in chronic kidney diseases, such as diabetic nephropathy, etc. The underlying mechanisms of how to decrease ECM deposition to improve diabetic nephropathy remain elusive. The present study investigated whether cyclopentanone compound H8 alleviated ECM over-deposition and fibrosis to prevent and treat diabetic nephropathy. HK-2 cell viability after treatment with H8 was measured by an MTT assay. ECM alterations and renal fibrosis were identified in vitro and in vivo. A pharmacological antagonist was used to detect associations between H8 and the p38 mitogen-activated protein kinase (p38MAPK) signaling pathway. H8 binding was identified through computer simulation methods. Studies conducted on high glucose and transforming growth factor β1 (TGF-β1)-stimulated HK-2 cells revealed that the p38MAPK inhibitor SB 202190 and H8 had similar pharmacological effects. In addition, excessive ECM accumulation and fibrosis in diabetic nephropathy were remarkably improved after H8 administration in vivo and in vitro. Finally, the two molecular docking models further proved that H8 is a specific p38MAPK inhibitor that forms a hydrogen bond with the LYS-53 residue of p38MAPK. The cyclopentanone compound H8 alleviated the over-deposition of ECM and the development of fibrosis in diabetic nephropathy by suppressing the TGF-β/p38MAPK axis.

Inhibition of S100A8/A9 ameliorates renal interstitial fibrosis in diabetic nephropathy

BackgroundRenal interstitial fibrosis (RIF) is one of the main features of diabetic nephropathy (DN), but the molecular mechanisms mediating RIF in DN has yet been fully understood. S100A8 and S100A9 are the proteins associated with immune and inflammation response. Here we reported the expression of S100A8 and S100A9 were significantly increased on tubular epithelial cells in diabetic kidneys through a proteomic analysis. MethodsWe detected the expression of S100A8/A9 in diabetic kidneys by using immunoblotting, real-time PCR and immunostaining. RNA silencing and overexpression were performed by using S100A8/A9 expression/knockdown lentivirus to investigate the connection between S100A8/A9 and epithelial to mesenchymal transition (EMT) process. We also identify the expression of TLR4/NFκB pathway-related molecules in the case mentioned above. Afterwards a CO-IP assay was used to verify that compound AB38b ameliorates the EMT by interfering S100A8/A9 expression. ResultsThe expression of S100A8 and S100A9 were significantly increased on tubular epithelial cells in diabetic kidneys. S100A8/A9 knocking-down alleviate and over-expression promote the renal interstitial fibrosis of diabetic mice. Mechanically, high levels of S100A8/A9 expression in tubular epithelial cells during diabetic condition activated the TLR4/NF-κB signal pathway which promoted the EMT process and finally led to RIF progression. S100A8/A9 knockdown ameliorated RIF of diabetic mice. Further experiments revealed that compound AB38b inhibited the EMT progression of tubular epithelial cells induced by S100A8/A9 through interfering the expressions of S100A8/A9. ConclusionsOur study suggest that abnormal expression of S100A8/A9 in the disease condition promotes EMT process and RIF through TLR4/NF-κB signal pathway. Using small molecular inhibitor AB38b to inhibit the abnormal expressions of S100A8/A9 might be a novel therapeutic strategy in treating DN.

Key Genetic Components of Fibrosis in Diabetic Nephropathy: An Updated Systematic Review and Meta-Analysis

Renal fibrosis (RF) constitutes the common end-point of all kinds of chronic kidney disease (CKD), regardless of the initial cause of disease. The aim of the present study was to identify the key players of fibrosis in the context of diabetic nephropathy (DN). A systematic review and meta-analysis of all available genetic association studies regarding the genes that are included in signaling pathways related to RF were performed. The evaluated studies were published in English and they were included in PubMed and the GWAS Catalog. After an extensive literature review and search of the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, eight signaling pathways related to RF were selected and all available genetic association studies of these genes were meta-analyzed. ACE, AGT, EDN1, EPO, FLT4, GREM1, IL1B, IL6, IL10, IL12RB1, NOS3, TGFB1, IGF2/INS/TH cluster, and VEGFA were highlighted as the key genetic components driving the fibrosis process in DN. The present systematic review and meta-analysis indicate, as key players of fibrosis in DN, sixteen genes. However, the results should be interpreted with caution because the number of studies was relatively small.

Statement of Retraction: Diminution of microRNA-98 alleviates renal fibrosis in diabetic nephropathy by elevating Nedd4L and inactivating TGF-β/Smad2/3 pathway

This article refers to:RETRACTED ARTICLE: Diminution of microRNA-98 alleviates renal fibrosis in diabetic nephropathy by elevating Nedd4L and inactivating TGF-β/Smad2/3 pathway

Cellular phenotypic transitions in diabetic nephropathy: An update.

Diabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetes and is the most common cause of end stage renal disease (ESRD). Renal fibrosis is the final pathological change in DN. It is widely believed that cellular phenotypic switching is the cause of renal fibrosis in diabetic nephropathy. Several types of kidney cells undergo activation and differentiation and become reprogrammed to express markers of mesenchymal cells or podocyte-like cells. However, the development of targeted therapy for DN has not yet been identified. Here, we discussed the pathophysiologic changes of DN and delineated the possible origins that contribute to myofibroblasts and podocytes through phenotypic transitions. We also highlight the molecular signaling pathways involved in the phenotypic transition, which would provide valuable information for the activation of phenotypic switching and designing effective therapies for DN.