The role of mitophagy in the development of chronic kidney disease.

Chronic kidney disease (CKD) represents a significant global health concern, with renal fibrosis emerging as a prevalent and ultimate manifestation of this condition. The absence of targeted therapies presents an ongoing and substantial challenge. Accumulating evidence suggests that the integrity and functionality of mitochondria within renal tubular epithelial cells (RTECs) often become compromised during CKD development, playing a pivotal role in the progression of renal fibrosis. Mitophagy, a specific form of autophagy, assumes responsibility for eliminating damaged mitochondria to uphold mitochondrial equilibrium. Dysregulated mitophagy not only correlates with disrupted mitochondrial dynamics but also contributes to the advancement of renal fibrosis in CKD. While numerous studies have examined mitochondrial metabolism, ROS (reactive oxygen species) production, inflammation, and apoptosis in kidney diseases, the precise pathogenic mechanisms underlying mitophagy in CKD remain elusive. The exact mechanisms through which modulating mitophagy mitigates renal fibrosis, as well as its influence on CKD progression and prognosis, have not undergone systematic investigation. The role of mitophagy in AKI has been relatively clear, but the role of mitophagy in CKD is still rare. This article presents a comprehensive review of the current state of research on regulating mitophagy as a potential treatment for CKD. The objective is to provide fresh perspectives, viable strategies, and practical insights into CKD therapy, thereby contributing to the enhancement of human living conditions and patient well-being.

[Research advances on the role of aerobic glycolysis in skin fibrosis diseases].

Skin fibrosis diseases mainly include hypertrophic scar, keloid, and systemic sclerosis, etc. The main pathological features are excessive activation of fibroblasts and abnormal deposition of extracellular matrix. In recent years, studies have shown that aerobic glycolysis is closely related to the occurrence and development of skin fibrosis diseases. Drugs targeting aerobic glycolysis has provided new ideas for skin anti-fibrosis treatment. This article reviews the role of enzymes and products related to aerobic glycolysis in the occurrence and development of skin fibrosis diseases and the drugs targeting aerobic glycolysis for the treatment of skin fibrosis diseases.

Attenuating Renal Interstitial Fibrosis by Shenqi Pill via Reducing Inflammation Response Regulated by NF-κB Pathway In Vitro and In Vivo.

INTRODUCTION: One of the most significant clinical features of chronic  kidney disease is renal interstitial fibrosis (RIF). This study aimed  to investigate the role and mechanism of Shenqi Pill (SQP) on RIF. METHODS: RIF model was established by conducting unilateral  ureteral obstruction (UUO) surgery on rat or stimulating human  kidney-2 (HK-2) cell with transforming growth factor ß1 (TGFß1).  After modeling, the rats in the SQP low dose group (SQP-L), SQP  middle dose group (SQP-M) and SQP high dose group (SQP-H)  were treated with SQP at 1.5, 3 or 6 g/kg/d, and the cells in the  TGFß1+SQP-L/M/H were treated with 2.5%, 5%, 10% SQP-containing  serum. In in vivo assays, serum creatinine (SCr) and blood urea  nitrogen (BUN) content were measured, kidney histopathology  was evaluated., and α-smooth muscle actin (α-SMA) expression  was detected by immunohistochemistry. Interleukin-1ß (IL-1ß),  interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) content,  inhibitor of kappa B alpha (IKBα) and P65 phosphorylation were  assessed. Meanwhile, cell viability, inflammatory cytokines content,  α-SMA expression, IKBα and P65 phosphorylation were detected  in vitro experiment.  Results. SQP exhibited reno-protective effect by decreasing SCr  and BUN content, improving renal interstitial damage, blunting  fibronectin (FN) and α-SMA expression in RIF rats. Similarly, after  the treatment with SQP-containing serum, viability and α-SMA  expression were remarkably decreased in TGFß1-stimulated HK-2  cell. Furthermore, SQP markedly down-regulated IL-1ß, IL-6, and  TNF-α content, IKBα and RelA (P65) phosphorylation both in vivo and in vitro.  Conclusion. SQP has a reno-protective effect against RIF in vivo and in vitro, and the effect is partly linked to nuclear factor-kappa  B (NF-κB) pathway related inflammatory response, which indicates  that SQP may be a candidate drug for RIF. DOI: 10.52547/ijkd.7546.

Microvesicles from Mesenchymal Stem Cells Overexpressing MiR-34a Ameliorate Renal Fibrosis In Vivo.

INTRODUCTION: We recently discovered that microvesicles (MVs)  derived from mesenchymal stem cells (MSCs) overexpressing  miRNA-34a can alleviate experimental kidney injury in mice. In  this study, we further explored the effects of miR34a-MV on renal  fibrosis in the unilateral ureteral obstruction (UUO) models.  Methods. Bone marrow MSCs were modified by lentiviruses  overexpressing miR-34a, and MVs were collected from the  supernatants of MSCs. C57BL6/J mice were divided into control,  unilateral ureteral obstruction (UUO), UUO + MV, UUO + miR-34aMV and UUO + miR-34a-inhibitor-MV groups. MVs were injected  to mice after surgery. The mice were then euthanized on day 7  and 14 of modeling, and renal tissues were collected for further  analyses by Hematoxylin and eosin, Masson's trichrome,  and Immunohistochemical (IHC) staining.  Results. The UUO + MV group exhibited a significantly reduced  degree of renal interstitial fibrosis with inflammatory cell infiltration,  tubular epithelial cell atrophy, and vacuole degeneration compared  with the UUO group. Surprisingly, overexpressing miR-34a enhanced  these effects of MSC-MV on the UUO mice.  Conclusion. Our study demonstrates that miR34a further enhances  the effects of MSC-MV on renal fibrosis in mice through the  regulation of epithelial-to-mesenchymal transition (EMT) and  Notch pathway. miR-34a may be a candidate molecular therapeutic  target for the treatment of renal fibrosis. DOI: 10.52547/ijkd.7673.

Reproducibility and prognostic ability of chronicity parameters in kidney biopsy - Comprehensive evaluation comparing microscopy and artificial intelligence in digital pathology.

INTRODUCTION: Semi-quantitative scoring of various parameters in renal biopsy is accepted as an important tool to assess disease activity and prognostication. There are concerns on the impact of interobserver variability in its prognostic utility, generating a need for computerized quantification. METHODS: We studied 94 patients with renal biopsies, 45 with native diseases and 49 transplant patients with index biopsies for Polyomavirus nephropathy. Chronicity scores were evaluated using two methods. A standard definition diagram was agreed after international consultation and four renal pathologists scored each parameter in a double-blinded manner. Interstitial fibrosis (IF) score was assessed with five different computerized and AI-based algorithms on trichrome and PAS stains. RESULTS: There was strong prognostic correlation with renal function and graft outcome at a median follow-up ranging from 24 to 42 months respectively, independent of moderate concordance for pathologists scores. IF scores with two of the computerized algorithms showed significant correlation with estimated glomerular filtration rate (eGFR) at biopsy but not at the end of follow-up. There was poor concordance for AI based platforms. CONCLUSION: Chronicity scores are robust prognostic tools despite interobserver reproducibility. AI-algorithms have absolute precision but are limited by significant variation when different hardware and software algorithms are used for quantification.

Fibrosis and expression of extracellular matrix proteins in human interventricular septum in aortic valve stenosis and regurgitation.

Valvular heart disease leads to ventricular pressure and/or volume overload. Pressure overload leads to fibrosis, which might regress with its resolution, but the limits and details of this reverse remodeling are not known. To gain more insight into the extent and nature of cardiac fibrosis in valve disease, we analyzed needle biopsies taken from the interventricular septum of patients undergoing surgery for valve replacement focusing on the expression and distribution of major extracellular matrix protein involved in this process. Proteomic analysis performed using mass spectrometry revealed an excellent correlation between the expression of collagen type I and III, but there was little correlation with the immunohistochemical staining performed on sister sections, which included antibodies against collagen I, III, fibronectin, sarcomeric actin, and histochemistry for wheat germ agglutinin. Surprisingly, the immunofluorescence intensity did not correlate significantly with the gold standard for fibrosis quantification, which was performed using Picrosirius Red (PSR) staining, unless multiplexed on the same tissue section. There was also little correlation between the immunohistochemical markers and pressure gradient severity. It appears that at least in humans, the immunohistochemical pattern of fibrosis is not clearly correlated with standard Picrosirius Red staining on sister sections or quantitative proteomic data, possibly due to tissue heterogeneity at microscale, comorbidities, or other patient-specific factors. For precise correlation of different types of staining, multiplexing on the same section is the best approach.

DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts.

Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A), play a pivotal role in driving clonal hematopoiesis of indeterminate potential (CHIP), and are associated with unfavorable outcomes in patients suffering from heart failure (HF). However, the precise interactions between CHIP-mutated cells and other cardiac cell types remain unknown. Here, we identify fibroblasts as potential partners in interactions with CHIP-mutated monocytes. We used combined transcriptomic data derived from peripheral blood mononuclear cells of HF patients, both with and without CHIP, and cardiac tissue. We demonstrate that inactivation of DNMT3A in macrophages intensifies interactions with cardiac fibroblasts and increases cardiac fibrosis. DNMT3A inactivation amplifies the release of heparin-binding epidermal growth factor-like growth factor, thereby facilitating activation of cardiac fibroblasts. These findings identify a potential pathway of DNMT3A CHIP-driver mutations to the initiation and progression of HF and may also provide a compelling basis for the development of innovative anti-fibrotic strategies.

New Insights into the Role of KLF10 in Tissue Fibrosis.

Fibrosis, characterized by excessive extracellular matrix accumulation, disrupts normal tissue architecture, causes organ dysfunction, and contributes to numerous chronic diseases. This review focuses on Krüppel-like factor 10 (KLF10), a transcription factor significantly induced by transforming growth factor-ß (TGF-ß), and its role in fibrosis pathogenesis and progression across various tissues. KLF10, initially identified as TGF-ß-inducible early gene-1 (TIEG1), is involved in key biological processes including cell proliferation, differentiation, apoptosis, and immune responses. Our analysis investigated KLF10 gene and protein structures, interaction partners, and context-dependent functions in fibrotic diseases. This review highlights recent findings that underscore KLF10 interaction with pivotal signaling pathways, such as TGF-ß, and the modulation of gene expression in fibrotic tissues. We examined the dual role of KLF10 in promoting and inhibiting fibrosis depending on tissue type and fibrotic context. This review also discusses the therapeutic potential of targeting KLF10 in fibrotic diseases, based on its regulatory role in key pathogenic mechanisms. By consolidating current research, this review aims to enhance the understanding of the multifaceted role of KLF10 in fibrosis and stimulate further research into its potential as a therapeutic target in combating fibrotic diseases.

Reconstruction of dermal layers evaluated by high-frequency ultrasound following treatment for skin fibrosis.

Background: Lymphedema is a chronic, progressive clinical condition that evolves with intense fibrosis, the most advanced stage of which is stage III (lymphostatic fibrosclerosis). Aim: The aim of the present study was to show the possibility to reconstruct the dermal layers with the intensive treatment of fibrosis using the Godoy method. Case description: A 55-year-old patient with an eight-year history of edema of the lower limb of the leg had constant episodes of erysipelas, despite regular treatments. The edema progressed continually, associated with a change in the color of the skin and the formation of a crust. Intensive treatment (eight hours per day for three weeks) was proposed with the Godoy method. The ultrasound was performed and results revealed substantial improvement in the skin, with the onset of the reconstruction of the dermal layers. Conclusion: It is possible to reconstruct the layers of the skin in fibrotic conditions caused by lymphedema.

Determination of Interstitial Collagen Deposition and Related Topography Using the Second Harmonic Generation-Based HistoIndex Platform.

Interstitial fibrosis is characterized by the increased deposition of extracellular matrix (ECM) components within the interstitial space of various organs, such as the kidneys, heart, lungs, liver, and skin. The primary component of interstitial fibrosis-related scarring is interstitial collagen. Therefore, the therapeutic application of anti-fibrotic medication hinges on the accurate measurement of interstitial collagen levels within tissue samples. Current histological measurement techniques for interstitial collagen are generally semi-quantitative in nature and only provide a ratio of collagen levels within tissues. However, the Genesis™ 200 imaging system and supplemental image analysis software, FibroIndex™, from HistoIndex™, is a novel, automated platform for imaging and characterizing interstitial collagen deposition and related topographical properties of the collagen structures within an organ, in the absence of any staining. This is achieved by using a property of light known as second harmonic generation (SHG). Using a rigorous optimization protocol, collagen structures in tissue sections can be imaged with a high degree of reproducibility and ensures homogeneity across all samples while minimizing the introduction of any imaging artefacts or photobleaching (decreased tissue fluorescence due to prolonged exposure to the laser). This chapter outlines the protocol that should be undertaken to optimize HistoIndex scanning of tissue sections, and the outputs that can be measured and analyzed using the FibroIndex™ software.

The Long Noncoding RNA H19 Promotes Fibrotic Processes in Lens Epithelial Cells.

Purpose: The purpose of this study was to investigate the role of lncRNA H19 in epithelial-mesenchymal transition (EMT) and its molecular mechanism in fibrotic cataracts. Methods: TGF-ß2-induced EMT was induced in human lens epithelial cell line (HLECs) and rat lens explants to mimic posterior capsular opacification (PCO) in vitro and in vivo. Anterior subcapsular cataract (ASC) was induced in C57BL/6J mice. The long noncoding RNA (lncRNA) H19 (H19) expression was detected by RT-qPCR. Whole-mount staining of lens anterior capsule was used to detect α-SMA and vimentin. Lentiviruses carrying shRNA or H19 vector were transfected in HLECs to knockdown or overexpress H19. Cell migration and proliferation were characterized by EdU, Transwell, and scratch assay. EMT level was detected by Western blotting and immunofluorescence. The rAAV2 carrying mouse H19 shRNA was injected into ASC model mouse anterior chambers as a gene therapy to determine its therapeutic potential. Results: PCO and ASC models were built successfully. We found H19 upregulation in PCO and ASC models in vivo and in vitro. Overexpression of H19 by lentivirus transfection increased cell migration, proliferation, and EMT. In addition, H19 knockdown by lentivirus suppressed cell migration, proliferation, and EMT levels in HLECs. Moreover, transfection of rAAV2 H19 shRNA alleviated fibrotic area in ASC mouse lens anterior capsules. Conclusions: Excessive H19 participates in lens fibrosis. Overexpression of H19 increases, whereas knockdown of H19 ameliorates HLECs migration, proliferation, and EMT. These results demonstrate H19 might be a potential target for fibrotic cataracts.

Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH.

BACKGROUND: Pegozafermin is a long-acting glycopegylated (pegylated with the use of site-specific glycosyltransferases) fibroblast growth factor 21 (FGF21) analogue in development for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia. The efficacy and safety of pegozafermin in patients with biopsy-proven noncirrhotic NASH are not well established. METHODS: In this phase 2b, multicenter, double-blind, 24-week, randomized, placebo-controlled trial, we randomly assigned patients with biopsy-confirmed NASH and stage F2 or F3 (moderate or severe) fibrosis to receive subcutaneous pegozafermin at a dose of 15 mg or 30 mg weekly or 44 mg once every 2 weeks or placebo weekly or every 2 weeks. The two primary end points were an improvement in fibrosis (defined as reduction by ≥1 stage, on a scale from 0 to 4, with higher stages indicating greater severity), with no worsening of NASH, at 24 weeks and NASH resolution without worsening of fibrosis at 24 weeks. Safety was also assessed. RESULTS: Among the 222 patients who underwent randomization, 219 received pegozafermin or placebo. The percentage of patients who met the criteria for fibrosis improvement was 7% in the pooled placebo group, 22% in the 15-mg pegozafermin group (difference vs. placebo, 14 percentage points; 95% confidence interval [CI], -9 to 38), 26% in the 30-mg pegozafermin group (difference, 19 percentage points; 95% CI, 5 to 32; P = 0.009), and 27% in the 44-mg pegozafermin group (difference, 20 percentage points; 95% CI, 5 to 35; P = 0.008). The percentage of patients who met the criteria for NASH resolution was 2% in the placebo group, 37% in the 15-mg pegozafermin group (difference vs. placebo, 35 percentage points; 95% CI, 10 to 59), 23% in the 30-mg pegozafermin group (difference, 21 percentage points; 95% CI, 9 to 33), and 26% in the 44-mg pegozafermin group (difference, 24 percentage points; 95% CI, 10 to 37). The most common adverse events associated with pegozafermin therapy were nausea and diarrhea. CONCLUSIONS: In this phase 2b trial, treatment with pegozafermin led to improvements in fibrosis. These results support the advancement of pegozafermin into phase 3 development. (Funded by 89bio; ENLIVEN ClinicalTrials.gov number, NCT04929483.).

[1, 25-(OH)2-VitD3 attenuates renal tubulointerstitial fibrosis in diabetic kidney disease by inhibiting Snail1-SMAD3/SMAD4 complex formation].

Objective To investigate the effect of 1, 25-(OH)2-VitD3 (VitD3) on renal tubuleinterstitial fibrosis in diabetic kidney disease. Methods NRK-52E renal tubular epithelial cells were divided into control group (5.5 mmol/L glucose medium treatment), high glucose group (25 mmol/L glucose medium treatment) and high glucose with added VitD3 group (25 mmol/L glucose medium combined with 10-8 mmol/L VitD3). The mRNA and protein expression of Snail1, SMAD3, SMAD4, α-SMA and E-cadherin in NRK-52E cells were detected by real-time quantitative PCR and Western blot analysis respectively. The expression and localization of Snail1, SMAD3 and SMAD4 were detected by immunofluorescence cytochemical staining. The binding of Snail1 with SMAD3/SMAD4 complex to the promoter of Coxsackie-adenovirus receptor (CAR) was detected by chromatin immunoprecipitation. The interaction among Snail1, SMAD3/SMAD4 and E-cadherin were detected by luciferase assay. Small interfering RNA (siRNA) was used to inhibit the expression of Snail1 and SMAD4, and the expression of mRNA of E-cadherin was detected by real-time quantitative PCR. SD rats were randomly divided into control group, DKD group and VitD3-treated group. DKD model was established by injection of streptozotocin (STZ) in DKD group and VitD3-treated group. After DKD modeling, VitD3-treated group was given VitD3 (60 ng/kg) intragastric administration. Control group and DKD group were given normal saline intragastric administration. In the DKD group and VitD3-treated group, insulin (1-2 U/kg) was injected subcutaneously to control blood glucose for 8 weeks. The mRNA and protein levels of Snail1, SMAD3, SMAD4, α-SMA and E-cadherin in renal tissues were detected by real-time quantitative PCR and Western blot analysis respectively. Immunohistochemistry was used to detect the expression and localization of Snail1, SMAD3, SMAD4, α-SMA and E-cadherin in renal tissue. Results Compared with the control group, the mRNA and protein expressions of Snail1, SMAD3, SMAD4 and α-SMA in NRK-52E cells cultured with high glucose and in DKD renal tissues were up-regulated, while E-cadherin expression was down-regulated. After the intervention of VitD3, the expression levels of Snail1, SMAD3, SMAD4, α-SMA and E-cadherin in the DKD model improved to be close to those in the control group. Chromatin immunoprecipitation showed that Snail1 and SMAD3/SMAD4 bound to CAR promoter IV, while VitD3 prevented Snail1 and SMAD3/SMAD4 from binding to CAR promoter IV. Luciferase assay confirmed the interaction among Snail1, SMAD3/SMAD4 and E-cadherin. After the mRNA of Snail1 and SMAD4 was inhibited by siRNA, the expression of E-cadherin induced by high glucose was up-regulated. Conclusion VitD3 could inhibit the formation of Snail1-SMAD3/SMAD4 complex and alleviate the renal tubulointerstitial fibrosis in DKD.

FUT1-mediated terminal fucosylation acts as a new target to attenuate renal fibrosis.

BACKGROUNDS: Renal fibrosis is a common pathologic process of most chronic kidney diseases (CKDs), becoming one of the major public health problems worldwide. Terminal fucosylation plays an important role in physiological homeostasis and pathological development. The present study aimed to explore the role of terminal fucosylation during kidney fibrogenesis and propose a possible anti-fibrosis treatment via suppressing aberrant terminal fucosylation. METHODS: We investigated the expression level of fucosyltransferase1 (FUT1) in CKD patients by using public database. Then, we further confirmed the level of terminal fucosylation by UEA-I staining and FUT1 expression in unilateral ureteral obstruction (UUO)-induced renal fibrosis mice. Immunostaining, qPCR, western blotting and wound healing assay were applied to reveal the effect of FUT1 overexpression in human kidney proximal tubular epithelial cell (HK-2). What's more, we applied terminal fucosylation inhibitor, 2-Deoxy-D-galactose (2-D-gal), to determine whether suppressing terminal fucosylation ameliorates renal fibrosis progression in vitro and in vivo. RESULTS: Here, we found that the expression of FUT1 significantly increased during renal fibrosis. In vitro experiments showed upregulation of epithelial-mesenchymal transition (EMT) after over-expression of FUT1 in HK-2. Furthermore, in vivo and in vitro experiments indicated that suppression of terminal fucosylation, especially on TGF-ßR I and II, could alleviate fibrogenesis via inhibiting transforming growth factor-ß (TGF-ß)/Smad signaling. CONCLUSIONS: The development of kidney fibrosis is attributed to FUT1-mediated terminal fucosylation, shedding light on the inhibition of terminal fucosylation as a potential therapeutic treatment against renal fibrosis.

Rinofima: reporte de un caso de Clínica Estrella / Rhinophyma: a case report of Clínica Estrella

La rinofima es una patología que se caracteriza por presentar hipertrofia de las glándulas sebáceas con proliferación de tejido fibroso, donde la nariz toma un aspecto lobulado dando como resultado la deformidad de la punta nasal; es una forma de rosácea. La prevalencia de esta variedad de rosácea es de aproximadamente un 5-7% en la población y con predominio en el sexo masculino de la quinta a séptima década de vida. Su etiología no se conoce con exactitud. Se presenta el caso de un paciente masculino de 84 años, con antecedentes patológicos de hipertensión arterial e hipotiroidismo; su lesión inició hace 10 años, como una lesión eritematosa con presencia de telangiectasia a nivel de alas y punta nasal, no dolorosa. Se realizó tratamiento con bisturí frío y radiofrecuencia, se realizaron cortes transversales hasta dejar el lecho desprovisto del tumor y finalmente se usó radiofrecuencia en toda la superficie de la lesión restante. Se realizó el procedimiento ambulatorio sin complicaciones inmediatas o tardías

Rhinophyma is a pathology characterized by hypertrophy of the sebaceous glands with proliferation of fibrous tissue, the nose has a lobed appearance, as a result there is a deformity of the nasal tip; rhinophyma is a form of rosacea. The prevalence of this variety of rosacea is approximately 5-7% in the population and predominantly in males from the fifth to seventh decade of life, the etiology is not well known, however there are several predisposing genetic and environmental factors. We present the case of an 84-year-old male patient with a pathological history of arterial hypertension and hypothyroidism; his lesion began 10 years ago, as an erythematous lesion with presence of telangiectasia in the wings and nasal tip, not painful. Treatment was performed with a cold scalpel and radiofrequency, transverse cuts were made until the tumor was gone, and finally radiofrequency was used on the entire surface of the remaining lesion. The outpatient procedure was performed without immediate or late complications.

Metabolic reprogramming heterogeneity in chronic kidney disease.

Fibrosis driven by excessive accumulation of extracellular matrix (ECM) is the hallmark of chronic kidney disease (CKD). Myofibroblasts, which are the cells responsible for ECM production, are activated by cross talk with injured proximal tubule and immune cells. Emerging evidence suggests that alterations in metabolism are not only a feature of but also play an influential role in the pathogenesis of renal fibrosis. The application of omics technologies to cell-tracing animal models and follow-up functional data suggest that cell-type-specific metabolic shifts have particular roles in the fibrogenic response. In this review, we cover the main metabolic reprogramming outcomes in renal fibrosis and provide a future perspective on the field of renal fibrometabolism.

Fibrosis: Types, Effects, Markers, Mechanisms for Disease Progression, and Its Relation with Oxidative Stress, Immunity, and Inflammation.

Most chronic inflammatory illnesses include fibrosis as a pathogenic characteristic. Extracellular matrix (ECM) components build up in excess to cause fibrosis or scarring. The fibrotic process finally results in organ malfunction and death if it is severely progressive. Fibrosis affects nearly all tissues of the body. The fibrosis process is associated with chronic inflammation, metabolic homeostasis, and transforming growth factor-ß1 (TGF-ß1) signaling, where the balance between the oxidant and antioxidant systems appears to be a key modulator in managing these processes. Virtually every organ system, including the lungs, heart, kidney, and liver, can be affected by fibrosis, which is characterized as an excessive accumulation of connective tissue components. Organ malfunction is frequently caused by fibrotic tissue remodeling, which is also frequently linked to high morbidity and mortality. Up to 45% of all fatalities in the industrialized world are caused by fibrosis, which can damage any organ. Long believed to be persistently progressing and irreversible, fibrosis has now been revealed to be a very dynamic process by preclinical models and clinical studies in a variety of organ systems. The pathways from tissue damage to inflammation, fibrosis, and/or malfunction are the main topics of this review. Furthermore, the fibrosis of different organs with their effects was discussed. Finally, we highlight many of the principal mechanisms of fibrosis. These pathways could be considered as promising targets for the development of potential therapies for a variety of important human diseases.

Cardiomyocyte-specific Peli1 contributes to the pressure overload-induced cardiac fibrosis through miR-494-3p-dependent exosomal communication.

Cardiac fibrosis is an essential pathological process in pressure overload (PO)-induced heart failure. Recently, myocyte-fibroblast communication is proven to be critical in heart failure, in which, pathological growth of cardiomyocytes (CMs) may promote fibrosis via miRNAs-containing exosomes (Exos). Peli1 regulates the activation of NF-κB and AP-1, which has been demonstrated to engage in miRNA transcription in cardiomyocytes. Therefore, we hypothesized that Peli1 in CMs regulates the activation of cardiac fibroblasts (CFs) through an exosomal miRNA-mediated paracrine mechanism, thereby promoting cardiac fibrosis. We found that CM-conditional deletion of Peli1 improved PO-induced cardiac fibrosis. Moreover, Exos from mechanical stretch (MS)-induced WT CMs (WT MS-Exos) promote activation of CFs, Peli1-/- MS-Exos reversed it. Furthermore, miRNA microarray and qPCR analysis showed that miR-494-3p was increased in WT MS-Exos while being down regulated in Peli1-/- MS-Exos. Mechanistically, Peli1 promoted miR-494-3p expression via NF-κB/AP-1 in CMs, and then miR-494-3p induced CFs activation by inhibiting PTEN and amplifying the phosphorylation of AKT, SMAD2/3, and ERK. Collectively, our study suggests that CMs Peli1 contributes to myocardial fibrosis via CMs-derived miR-494-3p-enriched exosomes under PO, and provides a potential exosomal miRNA-based therapy for cardiac fibrosis.

Salvianolic acid B attenuates tubulointerstitial fibrosis by inhibiting EZH2 to regulate the PTEN/Akt pathway.

CONTEXT: Salvianolic acid B (SAB) can alleviate renal fibrosis and improve the renal function. OBJECTIVE: To investigate the effect of SAB on renal tubulointerstitial fibrosis and explore its underlying mechanisms. MATERIALS AND METHODS: Male C57 mice were subjected to unilateral ureteric obstruction (UUO) and aristolochic acid nephropathy (AAN) for renal fibrosis indication. Vehicle or SAB (10 mg/kg/d, i.p.) were given consecutively for 2 weeks in UUO mice while 4 weeks in AAN mice. The serum creatinine (Scr) and blood urine nitrogen (BUN) were measured. Masson's trichrome staining and the fibrotic markers (FN and α-SMA) were used to evaluate renal fibrosis. NRK-49F cells exposed to 2.5 ng/mL TGF-ß were treated with SAB in the presence or absence of 20 µM 3-DZNep, an inhibitor of EZH2. The protein expression of EZH2, H3k27me3 and PTEN/Akt signaling pathway in renal tissue and NRK-49F cells were measured by Western blots. RESULTS: SAB significantly improved the levels of Scr by 24.3% and BUN by 35.7% in AAN mice. SAB reduced renal interstitial collagen deposition by 34.7% in UUO mice and 72.8% in AAN mice. Both in vivo and in vitro studies demonstrated that SAB suppressed the expression of FN and α-SMA, increased PTEN and decreased the phosphorylation of Akt, which were correlated with the down-regulation of EZH2 and H3k27me3. The inhibition of EZH2 attenuated the anti-fibrotic effects of SAB in NRK-49Fs. CONCLUSION: SAB might have therapeutic potential on renal fibrosis of CKD through inhibiting EZH2, which encourages further clinical trials.