Chronic kidney disease (CKD) causes progressive and irreversible damage to the kidneys. Renal biopsies are essential for diagnosing the etiology and prognosis of CKD, while accurate quantification of tubulo-interstitial injuries from whole slide images (WSIs) of renal biopsy specimens is challenging with visual inspection alone.

We develop a deep learning-based method named DLRS to quantify interstitial fibrosis and inflammatory cell infiltration as tubulo-interstitial injury scores, from WSIs of renal biopsy specimens. DLRS segments WSIs into non-tissue areas, glomeruli, tubules, interstitium, and arteries, and detects interstitial nuclei. It then quantifies these tubulo-interstitial injury scores using the segmented tissues and detected nuclei.

Applied to WSIs from 71 Japanese CKD patients with diabetic nephropathy or benign nephrosclerosis, DLRS-derived scores show concordance with nephrologists' evaluations. Notably, the DLRS-derived fibrosis score has a higher correlation with the estimated glomerular filtration rate (eGFR) at biopsy than scores from nephrologists' evaluations. Validated on WSIs from 28 Japanese tubulointerstitial nephritis patients and 49 European-ancestry patients with nephrosclerosis, DLRS-derived scores show a significant correlation with eGFR. In an expanded analysis of 238 Japanese CKD patients, including 167 from another hospital, deviations in eGFR from expected values based on DLRS-derived scores correlate with annual eGFR decline after biopsy. Inclusion of these deviations and DLRS-derived fibrosis scores improve predictions of the annual eGFR decline.

DLRS-derived tubulo-interstitial injury scores are concordant with nephrologists' evaluations and correlated with eGFR across different populations and institutions. The effectiveness of DLRS-derived scores for predicting annual eGFR decline highlights the potential of DLRS as a predictor of renal prognosis.

Olfactory receptors (ORs), taste receptors and opsins are well-known for their pivotal roles in mediating the senses of smell, taste and sight, respectively. However, in the past two decades, research has shown that these sensory receptors also regulate physiological processes in a variety of non-sensory tissues. Although ORs, taste receptors and opsins have all been shown to have physiological roles beyond their traditional locations, most work in the kidney has focused on ORs. To date, renal ORs have been shown to have roles in blood pressure regulation (OLFR78 and OLFR558) and glucose homeostasis (OLFR1393). However, sensory receptors remain drastically understudied outside of traditional sensory systems, in part because of inherent challenges in studying these receptors. Increased knowledge of the physiological and pathophysiological roles of sensory receptors has the potential to substantially improve understanding of the function of numerous organs and systems, including the kidney. In addition, most sensory receptors are G protein-coupled receptors, which are considered to be the most druggable class of proteins, and thus could potentially be exploited as future therapeutic targets.

Fibrosis represents a terminal pathological manifestation encountered in numerous chronic diseases. The process involves the persistent infiltration of inflammatory cells, the transdifferentiation of fibroblasts into myofibroblasts, and the excessive deposition of extracellular matrix (ECM) within damaged tissues, all of which are characteristic features of organ fibrosis. Extensive documentation exists on fibrosis occurrence in vital organs such as the liver, heart, lungs, kidneys, and skeletal muscles, elucidating its underlying pathological mechanisms. Regular exercise is known to confer health benefits through its anti-inflammatory, antioxidant, and anti-aging effects. Notably, exercise exerts anti-fibrotic effects by modulating multiple pathways, including transforming growth factor-β1/small mother decapentaplegic protein (TGF-β1/Samd), Wnt/β-catenin, nuclear factor kappa-B (NF-kB), reactive oxygen species (ROS), microRNAs (miR-126, miR-29a, miR-101a), and exerkine (FGF21, irisin, FSTL1, and CHI3L1). Therefore, this paper aims to review the specific role and molecular mechanisms of exercise as a potential intervention to ameliorate organ fibrosis.

Renal fibrosis is closely related to the prognosis of chronic kidney disease (CKD). The increase in cGMP reduces renal fibrosis. Soluble guanylate cyclase (sGC) and phosphodiesterase (PDE) are key enzymes that maintain cGMP levels. BAY 41-8543 (1 mg/kg/day) and/or BAY 73-6691 (1 mg/kg/day) were used to treat 5/6 nephrectomized rats for 13 weeks. 5/6 Nephrectomy caused an increase in cystatin C, proteinuria and glomerulosclerosis and renal interstitial fibrosis. Neither sGC stimulation nor PDE9 inhibition alone improved kidney function and morphology, whereas BAY 41-8543 in combination with BAY 73-6691 attenuated renal interstitial fibrosis. This beneficial effect could not be explained by alterations in blood pressure and the renal immune system. BAY 41-8543 in combination with BAY 73-6691 had no effect on renal macrophage, CD4 + T-cell and CD8 + T-cell in the late-stage of 5/6 nephrectomy. RNA sequencing revealed BAY 41-8543 in combination with BAY 73-6691 down-regulated the expression of fibrosis-related genes such as Collagen Type I Alpha 1, Collagen Type III Alpha 1 Chain and Collagen Type XIV Alpha 1 Chain. sGC stimulator combined with PDE9 inhibitor attenuated renal fibrosis in 5/6 nephrectomized rats by down-regulating fibrosis-related gene expression. This novel approach of using low-dose combination therapies to minimize side effects while maintaining therapeutic efficacy offers a promising strategy for the treatment of CKD.

To determine if the oral gonadotropin-releasing hormone antagonist relugolix affects leiomyoma extracellular matrix production through the transforming growth factor-beta (TGF-β) pathway.

Laboratory study.

None.

Exposure of human leiomyoma cells to TGF-β and/or relugolix.

Production of TGF-β, pSMAD2/3, SMAD2/3, collagen 1A1 (COL1A1), fibronectin (FN1), and versican (VCAN) in treated and untreated leiomyoma cells.

Transforming growth factor-beta 3 production decreased at 24 hours with relugolix 10 nM (0.80 ± 0.09-fold) and 100 nM (0.86 ± 0.06-fold) and at 48 hours with relugolix 1 nM (0.86 ± 0.05-fold) and 100 nM (0.86 ± 0.06-fold). pSMAD2/3 production decreased at 24 hours with relugolix 1 nM (0.71 ± 0.01-fold), 10 nM (0.68 ± 0.01-fold), and 100 nM (0.41 ± 0.10-fold). Compared with relugolix treatment alone at the same concentration, combination treatment at 24 hours resulted in significantly increased COL1A1, FN1, and VCAN production with relugolix 1 nM, 10 nM, and 100 nM. At 48 hours, combination treatment resulted in significantly increased COL1A1, FN1, and VCAN production with relugolix 10 nM and 100 nM.

Relugolix regulated leiomyoma size by decreasing COL1A1, FN1, and VCAN production. This effect is at least partly through the TGF-β pathway.

Chronic kidney disease (CKD) is a global health concern caused by conditions such as hypertension, diabetes, hyperlipidemia, and chronic nephritis, leading to structural and functional kidney injury. Kidney fibrosis is a common outcome of CKD progression, with abnormal fatty acid oxidation (FAO) disrupting renal energy homeostasis and leading to functional impairments. This results in maladaptive repair mechanisms and the secretion of profibrotic factors, and exacerbates renal fibrosis. Understanding the molecular mechanisms of renal fibrosis is crucial for delaying CKD progression. Ferroptosis is a type of discovered an iron-dependent lipid peroxidation-regulated cell death. Notably, Ferroptosis contributes to tissue and organ fibrosis, which is correlated with the degree of renal fibrosis. This study aims to clarify the complex mechanisms of ferroptosis in renal parenchymal cells and explore how ferroptosis intervention may help alleviate renal fibrosis, particularly by addressing the gap in CKD mechanisms related to abnormal lipid metabolism under the ferroptosis context. The goal is to provide a new theoretical basis for clinically delaying CKD progression.

This study examined the possible defensive role of coenzyme Q10 (CQ10) against the impact of cadmium (Cd) and titanium dioxide nanoparticle (TNP) exposure on rat kidneys. Distilled water (1 mL/rat), corn oil (1 mL/rat), 10 mg CQ10/kg b.wt, 50 mg TNP/kg b.wt, 5 mg Cd/kg b.wt, TNP + Cd, or TNP + Cd + CQ10 was administered orally to seven groups of 70 male Sprague Dawley rats for 60 days. The findings demonstrated that TNP and/or Cd exposure considerably raised serum levels of several renal damage products, disturbed electrolyte balance including sodium, potassium, and calcium, decreased antioxidant enzyme concentration in the kidneys, and elevated malondialdehyde. In addition, rats exposed to TNP and/or Cd had significantly higher levels of renal titanium and Cd. In addition, rats exposed to TNP and/or Cd showed significant histopathological lesions and collagen deposition as revealed by H and E and Masson trichrome staining, respectively. The kidneys were severely damaged by the combined effects of TNP and Cd, although CQ10 greatly mitigated these effects. According to the study, exposure to TNP and Cd can damage the kidneys' function and structure, especially when combined. However, CQ10 can protect against TNP and Cd's nephrotoxic effects.

Kidney fibrosis causes irreversible structural damage in chronic kidney disease and is characterized by aberrant extracellular matrix (ECM) accumulation. Although glutamyl-prolyl-tRNA synthetase 1 (EPRS1) is a crucial enzyme involved in proline-rich protein synthesis, its role in kidney fibrosis remains unclear. The present study revealed that EPRS1 expression levels were increased in the fibrotic kidneys of patients and mice, especially in fibroblasts and proximal tubular epithelial cells, on the basis of single-cell analysis and immunostaining of fibrotic kidneys. Moreover, C57BL/6 EPRS1tm1b heterozygous knockout (Eprs1+/-) and pharmacological EPRS1 inhibition with the first-in-class EPRS1 inhibitor DWN12088 protected against kidney fibrosis and dysfunction by preventing fibroblast activation and proximal tubular injury. Interestingly, in vitro assays demonstrated that EPRS1-mediated nontranslational pathways in addition to translational pathways under transforming growth factor β-treated conditions by phosphorylating SMAD family member 3 in fibroblasts and signal transducers and activators of transcription 3 in injured proximal tubules. EPRS1 knockdown and catalytic inhibition suppressed these pathways, preventing fibroblast activation, proliferation, and subsequent collagen production. Additionally, we revealed that EPRS1 caused mitochondrial damage in proximal tubules but that this damage was attenuated by EPRS1 inhibition. Our findings suggest that the EPRS1-mediated ECM accumulation induces kidney fibrosis via fibroblast activation and mitochondrial dysfunction. Therefore, targeting EPRS1 could be a potential therapeutic target for alleviating fibrotic injury in chronic kidney disease.

Imperatorin is a naturally occurring furocoumarin derivative found in traditional Chinese medicine Angelica dahurica for its anticancer, antihypertensive, and antidiabetic properties. Chronic kidney disease (CKD) is a global health issue, characterized by a high prevalence, significant morbidity and mortality, and a range of related complications.

This study aims to investigate the protective effects of imperatorin treatment and the specific underlying mechanisms in progressive CKD.

Imperatorin was orally administrated for 14 consecutive days to mice with unilateral ureteral obstruction (UUO) to investigate the renal pathological alternations, pro-inflammatory mediators, antioxidant response, and ferroptotic death signaling. Imperatorin was also tested in the erastin-induced injury of renal proximal tubular cells (NRK-52E). Cell viability, ferroptosis protein markers, erastin-induced oxidative stress, and lipid peroxidation were assessed.

In vivo, imperatorin treatment alleviated kidney histology alternations and attenuated the protein expression of fibrotic markers. Furthermore, imperatorin administration reduced inflammatory cell infiltration, and alleviated the oxidative stress burden by downregulating protein markers such as catalase, superoxide dismutase 2 (SOD-2), NADPH oxidase 4 (NOX-4), and thioredoxin reductase 1 (Trxr-1). It also mitigated ferroptosis markers such as glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11/cystine transporter (SLC7A11/xCT), and transferrin receptor 1 (TFR-1), and attenuated renal cell apoptosis. In vitro, imperatorin treatment effectively decreased erastin-induced feroptotic cell death, restored the antioxidant enzyme levels, and mitigated lipid peroxidation as well as the expression of ferroptosis-related markers (XCT, GPX4, and p-p53) in a dose-dependent manner.

Our finding demonstrated for the first time, that imperatorin treatment holds therapeutic potential in a UUO mouse model of CKD and inhibits the erastin-induced oxidative stress, ferroptosis, and subsequent lipid peroxidation in vitro. This highlights the potential of imperatorin as a future therapeutic target for ferroptosis to improve the progression of CKD.

Macaranga denticulata (MD) bark is commonly utilized in traditional medicine for diabetes prevention and treatment. The bark extract of MD is rich in prenyl or farnesyl flavonoids and stilbenes, which possess antioxidant properties. Although data suggest the potential therapeutic benefits of the use of MD in treating diabetic nephropathy (DN), the precise mechanisms underlying MD-initiated protective effects against DN are not well understood. This study aimed to assess the renoprotective properties of MD extract by examining renofibrosis inhibition, oxidative stress, and inflammation utilizing streptozotocin-induced DN male Sprague - Dawley rats. Diabetic rats were intraperitoneally injected with streptozotocin (STZ) to induce diabetes. After 6 days, these rats were orally administered MD extract (200 mg/kg/day) or metformin (200 mg/kg/day) for 14 days. The administration of MD extract significantly lowered blood glucose levels, restored body weight, and reduced urine levels of various biomarkers associated with kidney functions. Histopathological analysis revealed protective effects in both kidneys and pancreas. Further, MD extract significantly restored abnormalities in advanced glycation end products, oxidative stress biomarkers, and proinflammatory cytokine levels in STZ-treated rats. MD extract markedly reduced renal fibrosis biomarker levels, indicating recovery from renal injury, and reversed dysregulation of sirtuins and claudin-1 in the kidneys of rats with STZ-induced diabetes. In conclusion, data demonstrated the renoprotective role of MD extract, indicating plant extract's ability to suppress oxidative stress and regulate proinflammatory pathways during pathological changes in diabetic nephropathy.

Ischemia/reperfusion injury (IRI) causes cellular dysfunction and death in organs like the kidney, heart, and brain. It involves energy depletion during ischemia and oxidative stress, inflammation, and apoptosis during reperfusion. Kidney IRI often leads to acute kidney injury (AKI) in various clinical scenarios. The omentum, an adipose tissue with healing properties, has been used to treat injuries in different organs.

This study aimed to assess the omentum's healing effects on reducing IRI's adverse effects after renal ischemia in Wistar rats.

A total number of 36 male Wistar rats were used in a study on IRI-induced AKI. Rats were divided into 6 groups of normal kidneys wrapped with omentum "Sham-1" and "Sham-2," ischemic kidney wrapped with omentum as "OMT-1" and "OMT-2," and ischemic kidney without omentum as "Control-1" and "Control-2." Ischemia was induced by clamping the left renal artery for 45 minutes. The omentum was transposed onto the injured kidney in "OMT" group. After sacrifice at weeks 4 and 8, kidney histology and blood samples were analyzed for kidney function markers.

On the first day after surgery, there was an immediate increase in creatinine and blood urea nitrogen (BUN) levels, which then decreased by day 28. Both OMT groups showed significantly lower levels of creatinine and BUN compared to Control groups on day 1, but after 28 days differences were not statistically significant. Histological analysis using H&E and Masson's trichrome staining revealed significantly higher levels of inflammatory cell infiltration and hyperemia in the OMT groups. However, fibrosis and glomerular shrinkage were higher in the Control groups.

Using an omental flap significantly prevented fibrosis within the renal parenchyma, slow down the AKI progression, and potentially serving as a promising therapeutic strategy for kidney dysfunction.

Cardiorenal fibrosis is a common feature of chronic cardiovascular disease and recent data suggests that cytokines and chemokines may also drive fibrosis. Here we tested the hypothesis that CXCR7, a highly conserved chemokine receptor, contributes to cardiac and renal fibrosis. We generated an anti-mouse CXCR7-specific monoclonal antibody (CXCR7 mAb) and tested its anti-fibrotic actions in cardiorenal fibrosis induced using the deoxycorticosterone acetate/uni-nephrectomy (DOCA-UNX) model. CXCR7 mAb treatment (10 mg/kg, twice weekly for 6 weeks) significantly attenuated the development of cardiac and renal fibrosis, and reduced fibrotic and inflammatory gene expression levels, in the absence of an effect on blood pressure. Immunohistochemical analysis demonstrated an increase in the vascular expression of CXCR7 in DOCA-UNX-treated mice. This study demonstrated that a CXCR7 mediated pathway plays a significant role in cardiac and renal fibrosis induced by DOCA-UNX treatment. Accordingly, antagonism of CXCR7 may provide a therapeutic opportunity to mitigate against fibrosis in the setting of mineralocorticoid excess.

TGF-β stimulates CCN2 expression which in turn amplifies TGF-β signaling. This process promotes extracellular matrix production and accelerates the pathological progression of fibrotic diseases. Alternative splicing plays an important role in multiple disease development, while U2 small nuclear RNA auxiliary factor 2 (U2AF2) is an essential factor in the early steps of pre-mRNA splicing. However, the molecular mechanism underlying abnormal CCN2 expression upon TGF-β stimulation remains unclear. This study elucidates that SIRT4 acts as a master regulator for CCN2 expression in response to TGF-β by modulating U2AF2-mediated alternative splicing. Analyses of renal biopsy specimens from patients with CKD and mouse fibrotic kidney tissues revealed marked nuclear accumulation of SIRT4. The tubulointerstitial fibrosis was alleviated by global deletion or tubular epithelial cell (TEC)-specific knockout of Sirt4, and aggravated by adeno-associated virus-mediated SIRT4 overexpression in TECs. Furthermore, SIRT4 was found to translocate from the mitochondria to the cytoplasm through the BAX/BAK pore under TGF-β stimulation. In the cytoplasm, TGF-β activated the ERK pathway and induced the phosphorylation of SIRT4 at Ser36, which further promoted its interaction with importin α1 and subsequent nuclear translocation. In the nucleus, SIRT4 was found to deacetylate U2AF2 at K413, facilitating the splicing of CCN2 pre-mRNA to promote CCN2 protein expression. Importantly, exosomes containing anti-SIRT4 antibodies were found to effectively mitigate the UUO-induced kidney fibrosis in mice. Collectively, these findings indicated that SIRT4 plays a role in kidney fibrosis by regulating CCN2 expression via the pre-mRNA splicing.

Diabetic nephropathy (DN) is one of the serious microvascular complications of diabetes mellitus. During the progression of DN, the proliferation of glomerular mesangial cells (GMCs) leads to the deposition of excessive extracellular matrix (ECM) in the mesangial region, eventually resulting in glomerulosclerosis. Rutaecarpine (Rut), an alkaloid found in the traditional Chinese medicinal herb Fructus Evodiae (Euodia rutaecarpa (Juss.) Benth.), has many biological activities. However, its mechanism of action in DN remains unknown. This study used db/db mice and high glucose (HG)-treated mouse mesangial cells (SV40 MES-13) to evaluate the protective effects of Rut and underlying mechanisms on GMCs in DN. We found that Rut alleviated urinary albumin and renal function and significantly relieved renal pathological damage. In addition, Rut decreased the ECM production, and renal inflammation and suppressed the activation of TGF-β1/Smad3 and NF-κB signaling pathways in vitro and in vivo. Protein kinase CK2α (CK2α) was identified as the target of Rut by target prediction, molecular docking, and cellular thermal shift assay (CETSA), and surface plasmon resonance (SPR). Furthermore, Rut could not continue to play a protective role in HG-treated SV40 cells after silencing CK2α. In summary, this study is the first to find that Rut can suppress ECM production and inflammation in HG-treated SV40 cells by inhibiting the activation of TGF-β1/Smad3 and NF-κB signaling pathways and targeting CK2α. Thus, Rut can potentially become a novel treatment option for DN.

To evaluate the impact of coenzyme Q-10 (CoQ-10) on the dysregulated synthesis of extracellular matrix proteins mediated by transforming growth factor beta 3 (TGF-β3) in uterine leiomyomas.

Laboratory study.

University.

None.

Treatment of immortalized uterine myometrial and leiomyoma cells to TGF-β3 and CoQ-10.

The protein concentrations of collagen 1A1 (COL1A1), collagen 3A1 (COL3A1), collagen 11A1 (COL11A1), and fibronectin (FN1) were assessed through western blot analysis after treatment of immortalized uterine myometrial and leiomyoma cells with both transforming growth factor beta (TGF-β) 3 and concentrations of CoQ-10 at 10, 50, and 100 μM concurrently for 24 hours.

Immortalized uterine leiomyoma and myometrial cells exposed to TGF-β3 for 24 hours demonstrated a significant up-regulation of COL1A1, COL3A1, COL11A1, and FN1 compared with untreated cells. In leiomyoma cells, concurrent treatment with CoQ-10 over the same timeframe revealed a dose-dependent decrease in these protein concentrations compared with those in cells treated with TGF-β3 alone. At the highest concentration of 100 μM of CoQ-10, significant decreases in the amounts of COL1A1 (0.59 ± 0.10-fold), COL3A1 (0.46 ± 0.09-fold), COL11A1 (0.53 ± 0.09-fold), and FN1 (0.56 ± 0.09-fold) were observed. Similarly, myometrial cells exposed to both TGF-β3 and CoQ-10 demonstrated a dose-responsive decline in the amount of extracellular matrix protein compared with cells exposed to TGF-β3 alone. Significant reductions in the amounts of COL1A1 (0.75 ± 0.03-fold), COL3A1 (0.48 ± 0.06-fold), COL11A1 (0.38 ± 0.06), and FN1 (0.69 ± 0.04-fold) were appreciated at 100-μM CoQ-10.

Coenzyme Q-10 mitigated the aberrant production of key biomarkers of the extracellular matrix mediated by TGF-β3 in uterine leiomyomas. Our findings highlight a promising nonhormonal compound that can counteract the fibroproliferative process inherent to leiomyomas.

To investigate the role and molecular mechanism of miR-126 in unilateral ureteral occlusion (UUO). We used bioinformatics to analyse miRNAs specifically expressed in UUO. The mouse model of UUO was established using RAW264.7 cells cultured in vitro and in vivo. The mice were divided into control group, miR-126-NC (negative control) group and miR-126-KD (knockdown) group. Then the relative expression of miR-126 was detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), the renal fibrosis was detected by Masson staining, and the protein expression of CD68, collagen I and collagen III in the kidney was detected by immunofluorescence assay. Immunohistochemistry detects α-SMA expression. Moreover, Western blotting was performed to measure the expressions of p-PI3K, CD163, CD206, CD86, iNOS, IL-1β, p-FAK, p-Rac-1, p-IRS-1 and MMP9. The relative fluorescence intensity of F-actin and p-FAK was detected by immunofluorescence assay, and the phagocytosis ability of macrophages was determined by phagocytosis assay with fluorescent microspheres. Bioinformatics analysis reveals miR-126-specific overexpression in UUO. Successful transfection of miR-126-NC and miR-126-KD was confirmed by RT-PCR. The selective reduction of miR-126 was validated by Masson, immunohistochemistry and immunofluorescence staining to decrease the area of UUO-induced renal fibrosis and to lower the expression of CD68, α-SMA, collagen I, and collagen III. The reduction of iNOS expression may also be achieved with selective knockdown of miR-126, as verified by cell tests. enhances the phagocytic ability of macrophages and the expression of p-PI3K, CD206, p-FAK, F-actin, p-Rac-1, p-IRS-1 and MMP9. MiR-126 can inhibit the PI3K signaling pathway, promote M1 macrophage polarization, and suppress the activation of FAK and Rac-1, thus accelerating the progression of UUO.

Glomerulonephritis remains a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). We have reported that expression of HER2/ErbB2, a member of the EGFR family, is increased in kidneys of patients and mice with lupus nephritis. We therefore asked if EGFR-family inhibition could ameliorate murine lupus nephritis. We used lapatinib, an EGFR-ErbB2 dual kinase inhibitor in female lupus-prone NZBxW/F1 mice, in which lupus onset was accelerated by injecting an IFN-α-expressing adenovirus. Mice received lapatinib (75 mg/Kg) or vehicle from the beginning of the acceleration or after the mice developed severe proteinuria (>300 mg/dL). Autoantibodies, kidney disease and markers of fibrosis and wound healing were analyzed. Exposure to IFNα induced ErbB2 expression in the kidney of lupus prone mice. Lapatinib, administered before but not after renal disease onset, lowered autoantibody titers and lessened immune complex deposition in the kidney. However, lapatinib increased proteinuria, kidney fibrosis and mouse mortality. Lapatinib also inhibited an in vitro wound healing assay testing renal cells. Our results suggest that EGFR-ErbB2 dual kinase inhibitor lapatinib decreases autoimmunity but worsens renal disease in IFNα-accelerated lupus, by increasing fibrosis and inhibiting wound healing. Type I Interferons are highlighted as important regulators of HER2/ErbB2 expression in the kidney. Further studies are required to parse the beneficial aspects of EGFR inhibition on autoimmunity from its negative effects on wound healing in lupus nephritis.

Glomerular fibrosis is a tissue damage that occurs within the kidneys of chronic and diabetic kidney disease patients. Effective treatments are lacking, and the mechanism of glomerular damage reversal is poorly understood.

A mathematical model suitable for hypothesis-driven systems pharmacology of glomerular fibrosis in diabetes was developed from a previous model of interstitial fibrosis. The adapted model consists of a system of ordinary differential equations that models the complex disease etiology and progression of glomerular fibrosis in diabetes.

Within the scope of the mechanism incorporated, advanced glycation end products (AGE)-matrix proteins that are modified due to high blood glucose-were identified as major contributors to the delay in the recovery from glomerular fibrosis after glucose control. The model predicted that inhibition of AGE production is not an effective approach for accelerating the recovery from glomerular fibrosis. Further, the model predicted that treatment breaking down accumulated AGE is the most productive at reversing glomerular fibrosis. The use of the model led to the identification that glucose control and aminoguanidine are ineffective treatments for reversing advanced glomerular fibrosis because they do not remove accumulated AGE. Additionally, using the model, a potential explanation was generated for the lack of efficacy of alagebrium in treating advanced glomerular fibrosis, which is due to the inability of alagebrium to reduce TGF- β .

Using the mathematical model, a mechanistic understanding of disease etiology and complexity of glomerular fibrosis in diabetes was illuminated, and then hypothesis-driven explanations for the lack of efficacy of different pharmacological agents for treating glomerular fibrosis were provided. This understanding can enable the development of more efficacious therapeutics for treating kidney damage in diabetes.

The epithelial-to-mesenchymal transition (EMT) plays a key role in the pathogenesis of kidney fibrosis, and kidney fibrosis is associated with an adverse renal prognosis. Beta-mangostin (β-Mag) is a xanthone derivative obtained from mangosteens that is involved in the generation of antifibrotic and anti-oxidation effects. The purpose of this study was to examine the effects of β-Mag on renal tubulointerstitial fibrosis both in vivo and in vitro and the corresponding mechanisms involved. As shown through an in vivo study conducted on a unilateral ureteral obstruction mouse model, oral β-Mag administration, in a dose-dependent manner, caused a lesser degree of tubulointerstitial damage, diminished collagen I fiber deposition, and the depressed expression of fibrotic markers (collagen I, α-SMA) and EMT markers (N-cadherin, Vimentin, Snail, and Slug) in the UUO kidney tissues. The in vitro part of this research revealed that β-Mag, when co-treated with transforming growth factor-β1 (TGF-β1), decreased cell motility and downregulated the EMT (in relation to Vimentin, Snail, and N-cadherin) and phosphoryl-JNK1/2/Smad2/Smad3 expression. Furthermore, β-Mag co-treated with SB (Smad2/3 kinase inhibitor) or SP600125 (JNK kinase inhibitor) significantly inhibited the TGF-β1-associated downstream phosphorylation and activation of JNK1/2-mediated Smad2 targeting the Snail/Vimentin axis. To conclude, β-Mag protects against EMT and kidney fibrotic processes by mediating the TGF-β1/JNK/Smad2 targeting Snail-mediated Vimentin expression and may have therapeutic implications for renal tubulointerstitial fibrosis.

As common clinical-pathological processes, wound healing and tissue remodelling following injury or stimulation are essential topics in medical research. Promoting the effective healing of prolonged wounds, improving tissue repair and regeneration, and preventing fibrosis are important and challenging issues in clinical practice. Ferroptosis, which is characterized by iron overload and lipid peroxidation, is a nontraditional form of regulated cell death. Emerging evidence indicates that dysregulated metabolic pathways and impaired iron homeostasis play important roles in various healing and regeneration processes via ferroptosis. Thus, we review the intrinsic mechanisms of tissue repair and remodeling via ferroptosis in different organs and systems under various conditions, including the inflammatory response in skin wounds, remodeling of joints and cartilage, and fibrosis in multiple organs. Additionally, we summarize the common underlying mechanisms, key molecules, and targeted drugs for ferroptosis in repair and regeneration. Finally, we discuss the potential of therapeutic agents, small molecules, and novel materials emerging for targeting ferroptosis to promote wound healing and tissue repair and attenuate fibrosis.

Four undescribed guaiane sesquiterpenes, aquisinenoids I-L (2-5) and five known compounds were isolated from the resins of Aquilaria sinensis. Their structures were deduced based on spectroscopic data analysis, X-ray crystallography and ECD calculations. Biologically, compounds 1, 5, 6 and 9 showed anti-renal fibrosis activity, significantly reducing the levels of fibronectin, collagen I, and α-SMA. Compounds 2-4, 7 and 8 could reduce one or two of these proteins at non-toxic concentrations in TGF-β1 induced NRK-52E cells.

Matrix metalloproteinases (MMPs) are a group of zinc-dependent proteolytic metalloenzymes that are involved in numerous pathological conditions, including nephropathy. MMP9, a member of the MMPs family, is categorized as a constituent of the gelatinase B subgroup, and its involvement in extracellular matrix (ECM) remodeling and renal fibrosis highlights its importance in the development and progression of renal diseases. The exact role of MMP9 in the development of kidney diseases is still controversial. This study investigated the dual role of MMP9 in kidney injury, discussing its implications in the pathogenesis of kidney diseases and investigating the design and mechanism of MMP9 inhibitors based on previous studies. This study provides an effective basis for the development of novel and selective MMP9 inhibitors for treating renal diseases.

Hydrogen sulfide (H2S) is known as a chemical gas in nature with both enzymatic and non-enzymatic biosynthesis in different human organs. A couple of studies have demonstrated the function of H2S in regulating the homeostasis of the human body. Additionally, they have shown its synthesis, measurement, chemistry, protective effects, and interaction in various aspects of scientific evidence. Furthermore, many researches have demonstrated the beneficial impacts of H2S on genital organs and systems. According to various studies, it is recognized that H2S-producing enzymes and the endogenous production of H2S are expressed in male and female reproductive systems in different mammalian species. The main goal of this comprehensive review is to assess the potential therapeutic impacts of this gasotransmitter in the male and female urogenital system and find underlying mechanisms of this agent. This narrative review investigated the articles that were published from the 1970s to 2022. The review's primary focus is the impacts of H2S on the male and female urogenital system. Medline, CINAHL, PubMed, and Google scholar databases were searched. Keywords used in this review were "Hydrogen sulfide," "H2S," "urogenital system," and "urogenital tract". Numerous studies have demonstrated the therapeutic and protective effects of sodium hydrosulfide (Na-HS) as an H2S donor on male and female infertility disorders. Furthermore, it has been observed that H2S plays a significant role in improving different diseases such as ameliorating sperm parameters. The specific localization of H2S enzymes in the urogenital system provides an excellent opportunity to comprehend its function and role in various disorders related to this system. It is noteworthy that H2S has been demonstrated to be produced in endocrine organs and exhibit diverse activities. Moreover, it is important to recognize that alterations in H2S biosynthesis are closely linked to endocrine disorders. Therefore, hormones can be pivotal in regulating H2S production, and H2S synthesis pathways may aid in establishing novel therapeutic strategies. H2S possesses pharmacological effects on essential disorders, such as anti-inflammation, anti-apoptosis, and anti-oxidant activities, which render it a valuable therapeutic agent for human urogenital disease. Furthermore, this agent shows promise in ameliorating the detrimental effects of various male and female diseases. Despite the limited clinical research, studies have demonstrated that applying H2S as an anti-oxidant source could ameliorate adverse effects of different conditions in the urogenital system. More clinical studies are required to confirm the role of this component in clinical settings.

Rhodojaponin VI (R-VI) is the key compound of Rhododendron molle G. Don (Ericaceae) (RM) with effective clinical application in rheumatoid arthritis and chronic glomerulonephritis. In our study, we tried to explore the effect of R-VI on the rat model of membranous nephropathy.

The rat model of passive heymann nephritis (PHN) was established by injecting sheep anti-rat Fx1A serum at a single dose through the tail. The rats were orally administered R-VI (0.02 mg/kg) or FK506 (1 mg/kg) 1 day before PHN induction, which was kept for 4 weeks. Urine and blood samples as well as kidney tissue were collected for analysis. C5b-9-induced human podocyte cell (HPC) was employed for experiments in vitro.

R-VI could alleviate glomerulonephritis progression and podocyte injury in PHN rats, as indicated by the decreased proteinuria and the elevated level of albumin, accompanied with reduced immune deposits, reversed podocyte injury in the kidneys. Furthermore, R-VI suppressed murine double minute 2 (MDM2) expression without the alteration in the protein level of p53 and decreased Notch1 expression independent of Numb regulation. Pre-treatment with R-VI in C5b-9-induced HPC blocked MDM2/Notch1 signalling pathway.

Thus, R-VI ameliorates podocyte injury in rats with PHN, which was probably related with MDM2/Notch1 signalling pathway.

Renal interstitial fibrosis (RIF) is often associated with inflammatory cell infiltration and no effective therapy. Programmed death cell-1 (PD-1) and its ligand PD-L1 were playing critical roles in T cell coinhibition and exhaustion, but the role in RIF is unclear. Here the data analyses of serum from 122 IgA nephrology (IgAN) patients showed that high level of soluble PD-1(sPD-1) was an independent risk factor for RIF and renal function progression. PD-L1 was also overexpressed in renal interstitial tissues from both IgAN patients with high level of sPD-1 and the unilateral ureteral obstruction (UUO) mouse. PD-L1 was significantly overexpressed in HK-2 cells with upregulated collagen and α-SMA when stimulated by inflammation or hypoxia in vitro. Additionally, matrix metalloproteinases (MMP-2) could increase the level of sPD-1 in culture supernatant when added in co-culture system of HK-2 and jurkat cells, which implied serum sPD-1 of IgAN might be cleaved by MMP-2 from T cells infiltrated into the tubulointerstitial inflammatory microenvironment. Crucially, injection of PD-L1 fusion protein, the blocker of sPD-1, could ameliorate kidney fibrosis in UUO mice by increasing T cell coinhibition and exhaustion, suggesting the therapeutic potential of PD-L1 fusion targeting for renal fibrosis. Take together, it reveals a novel causal role of sPD-1 in serum and PD-L1 of renal interstitial tissues in the development of renal fibrosis of IgAN, and targeting sPD-1 in serum by PD-L1 fusion protein is a potential therapeutic approach to prevent renal fibrosis of IgAN.

Fibrosis is the excessive deposition of extracellular matrix in an organ or tissue that results from an impaired tissue repair in response to tissue injury or chronic inflammation. The progressive nature of fibrotic diseases and limited treatment options represent significant healthcare challenges. Despite the substantial progress in understanding the mechanisms of fibrosis, a gap persists translating this knowledge into effective therapeutics. Here, we discuss the critical mediators involved in fibrosis and the role of tranilast as a potential antifibrotic drug to treat fibrotic conditions. Tranilast, an antiallergy drug, is a derivative of tryptophan and has been studied for its role in various fibrotic diseases. These include scleroderma, keloid and hypertrophic scars, liver fibrosis, renal fibrosis, cardiac fibrosis, pulmonary fibrosis, and uterine fibroids. Tranilast exerts antifibrotic effects by suppressing fibrotic pathways, including TGF-β, and MPAK. Because it disrupts fibrotic pathways and has demonstrated beneficial effects against keloid and hypertrophic scars, tranilast could be used to treat other conditions characterized by fibrosis.

Renal fibrosis (RF) is one of the underlying pathological conditions leading to progressive loss of renal function and end-stage renal disease (ESRD). Over the years, various therapeutic approaches have been explored to combat RF and prevent ESRD. Despite significant advances in understanding the underlying molecular mechanism(s), effective therapeutic interventions for RF are limited. Current therapeutic strategies primarily target these underlying mechanisms to halt or reverse fibrotic progression. Inhibition of transforming growth factor-β (TGF-β) signaling, a pivotal mediator of RF has emerged as a central strategy to manage RF. Small molecules, peptides, and monoclonal antibodies that target TGF-β receptors or downstream effectors have demonstrated potential in preclinical models. Modulating the renin-angiotensin system and targeting the endothelin system also provide established approaches for controlling fibrosis-related hemodynamic changes. Complementary to pharmacological strategies, lifestyle modifications, and dietary interventions contribute to holistic management. This comprehensive review aims to summarize the underlying mechanisms of RF and provide an overview of the therapeutic strategies and novel antifibrotic agents that hold promise in its treatment.

Metabolic acidosis-induced kidney injury (MAKI) is asymptomatic and lack of clinical biomarkers in early stage, but rapidly progresses to severe renal fibrosis and ultimately results in end-stage kidney failure. Therefore, developing rapid and noninvasive strategies direct responsive to renal tubular acidic microenvironment rather than delayed biomarkers are essential for timely renoprotective interventions. Herein, we develop pH-responsive luminescent gold nanoparticles (p-AuNPs) in the second near-infrared emission co-coated with 2,3-dimethylaleic anhydride conjugated β-mercaptoethylamine and cationic 2-diethylaminoethanethiol hydrochloride, which showed sensitive pH-induced charge reversal and intrarenal self-assembly for highly sensitive and long-time (~24 h) imaging of different stages of MAKI. By integrating advantages of pH-induced intrarenal self-assembly and enhanced interactions between pH-triggered positively charged p-AuNPs and renal tubular cells, the early- and late-stage MAKI could be differentiated rapidly within 10 min post-injection (p.i.) with contrast index (CI) of 3.5 and 4.3, respectively. The corresponding maximum CI could reach 5.1 and 9.2 at 12 h p.i., respectively. Furthermore, p-AuNPs were demonstrated to effectively real-time monitor progressive recovery of kidney injury in MAKI mice after therapy, and also exhibit outstanding capabilities for drug screening. This pH-responsive strategy showed great promise for feedback on kidney dysfunction progression, opening new possibilities for early-stage diagnosis of pH-related diseases.

Chronic kidney disease (CKD) is characterized by impaired renal function and is associated with inflammation, oxidative stress, and fibrosis. Sheep milk contains several bioactive molecules with protective effects against inflammation and oxidative stress. In the current study, we investigated the potential renoprotective effects of sheep milk and the associated mechanisms of action in an adenine-induced CKD murine model. Sheep milk delayed renal chronic inflammation (e.g., significant reduction in levels of inflammatory factors Vcam1, Icam1, Il6, and Tnfa), fibrosis (significant reduction in levels of fibrosis factors Col1a1, Fn1, and Tgfb), oxidative stress (significant increase in levels of antioxidants and decrease in oxidative markers), mineral disorders, and renal injury in adenine-treated mice (e.g. reduced levels of kidney injury markers NGAL and KIM-1). The combined proteomics and metabolomics analyses showed that sheep milk may affect the metabolic processes of several compounds, including proteins, lipids, minerals, and hormones in mice with adenine-induced chronic kidney disease. In addition, it may regulate the expression of fibrosis-related factors and inflammatory factors through the JAK1/STAT3/HIF-1α signaling pathway, thus exerting its renoprotective effects. Therefore, sheep milk may be beneficial for patients with CKD and should be evaluated in preclinical and clinical studies.

Metformin has been used in the management of diabetes for decades. It is an effective, low-cost intervention with a well-established safety profile. Emerging evidence suggests that metformin targets a number of pathways that lead to chronic kidney damage, and long-term use may, therefore, slow the rate of kidney function decline and chronic kidney disease (CKD) progression.

To evaluate the effect of metformin therapy on kidney function decline in patients with CKD with or without diabetes mellitus and assess the safety and dose tolerability in this population.

We searched the Cochrane Kidney and Transplant Register of Studies up to 19 July 2023 with assistance from an Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov.

We included randomised controlled trials (RCTs) that reported kidney-related outcomes with a minimum duration of 12 months delivery of the metformin intervention and whose eligibility criteria included adult participants with either i) a diagnosis of CKD of any aetiology and/or ii) those with a diagnosis of diabetes mellitus. Comparisons included placebo, no intervention, non-pharmacological interventions, other antidiabetic medications or any other active control. Studies that included patients on any modality of kidney replacement therapy were excluded.

Two authors independently carried out data extraction using a standard data extraction form. The methodological quality of the included studies was assessed using the Cochrane risk of bias tool. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

This review included 11 studies reporting on 8449 randomised participants. Studies were conducted in patient populations with Autosomal Dominant Polycystic Kidney Disease (ADPKD) (four studies) or diabetes mellitus (seven studies). Six studies compared metformin with no active control, four studies compared metformin with active controls (rosiglitazone, glyburide, pioglitazone, or glipizide), and one study included treatment arms that randomised to either metformin, diet and lifestyle modifications, or other antidiabetic therapies. The risk of bias in included studies varied; two studies were abstract-only publications and were judged to have a high risk of bias in most domains. Other included publications were judged to have a low risk of bias in most domains. Across comparisons, GRADE evaluations for most outcomes were judged as low or very low certainty, except for those relating to side effects, tolerance, and withdrawals, which were judged as moderate certainty. The evidence suggests that compared to placebo, metformin may result in i) a slightly smaller decline in kidney function (3 studies, 505 participants: MD 1.92 mL/min, 95% CI 0.33 to 3.51; I2 = 0%; low certainty), ii) very uncertain effects on the incidence of kidney failure (1 study, 753 participants: RR 1.20, 95% CI 0.17 to 8.49), iii) little or no effect on death (3 studies, 865 participants: RR 1.00, 95% CI 0.76 to 1.32; I2 = 0%; moderate certainty), iv) little or no effect on the incidence of serious adverse events (3 studies, 576 participants: RR 1.15, 95% CI 0.76 to 1.72; I2 = 0%; moderate certainty), and v) likely higher incidence of intolerance leading to study withdrawal than placebo (4 studies, 646 participants: RR 2.19, 95% CI 1.46 to 3.27; I2 = 0%; moderate certainty). The certainty of the evidence for proteinuria was very uncertain. Compared to other active controls (rosiglitazone, glyburide, pioglitazone, or glipizide), metformin i) demonstrated very uncertain effects on kidney function decline, ii) may result in little or no difference in death (3 studies, 5608 participants: RR 0.95 95% CI 0.63 to 1.43; I2 = 0%; low certainty), iii) probably results in little or no difference in intolerance leading to study withdrawal (3 studies, 5593 participants: RR 0.92, 95% CI, 0.79 to 1.08; I2 = 0%; moderate certainty), iv) probably results in little or no difference in the incidence of serious adverse events (2 studies, 5545 participants: RR 1.16, 95% CI 0.79 to 1.71; I2 = 0%; moderate certainty), and v) may increase the urinary albumin-creatinine ratio (2 studies, 3836 participants: MD 14.61, 95% CI 8.17 to 21.05; I2 = 0%; low certainty). No studies reported the incidence of kidney failure.

This review highlights the lack of RCTs reporting on the effects of metformin on kidney function, particularly in patients with CKD. Future research in this field requires adequately powered RCTs comparing metformin to placebo or standard care in those with CKD. Seven ongoing studies were identified in this review, and future updates, including their findings, may further inform the results of this review.

Kidney ultrasound (US) images are primarily employed for diagnosing different renal diseases. Among them, one is renal localization and detection, which can be carried out by segmenting the kidney US images. However, kidney segmentation from US images is challenging due to low contrast, speckle noise, fluid, variations in kidney shape, and modality artifacts. Moreover, well-annotated US datasets for renal segmentation and detection are scarce. This study aims to build a novel, well-annotated dataset containing 44,880 US images. In addition, we propose a novel training scheme that utilizes the encoder and decoder parts of a state-of-the-art segmentation algorithm. In the pre-processing step, pixel intensity normalization improves contrast and facilitates model convergence. The modified encoder-decoder architecture improves pyramid-shaped hole pooling, cascaded multiple-hole convolutions, and batch normalization. The pre-processing step gradually reconstructs spatial information, including the capture of complete object boundaries, and the post-processing module with a concave curvature reduces the false positive rate of the results. We present benchmark findings to validate the quality of the proposed training scheme and dataset. We applied six evaluation metrics and several baseline segmentation approaches to our novel kidney US dataset. Among the evaluated models, DeepLabv3+ performed well and achieved the highest dice, Hausdorff distance 95, accuracy, specificity, average symmetric surface distance, and recall scores of 89.76%, 9.91, 98.14%, 98.83%, 3.03, and 90.68%, respectively. The proposed training strategy aids state-of-the-art segmentation models, resulting in better-segmented predictions. Furthermore, the large, well-annotated kidney US public dataset will serve as a valuable baseline source for future medical image analysis research.

Renal fibrosis, specifically tubulointerstitial fibrosis, represents the predominant pathological consequence observed in the context of progressive chronic kidney conditions. The pathogenesis of renal fibrosis encompasses a multifaceted interplay of mechanisms, including but not limited to interstitial fibroblast proliferation, activation, augmented production of extracellular matrix (ECM) components, and impaired ECM degradation. Notably, mitochondria, the intracellular organelles responsible for orchestrating biological oxidation processes in mammalian cells, assume a pivotal role within this intricate milieu. Mitochondrial dysfunction, when manifest, can incite a cascade of events, including inflammatory responses, perturbed mitochondrial autophagy, and associated processes, ultimately culminating in the genesis of renal fibrosis. This comprehensive review endeavors to furnish an exegesis of mitochondrial pathophysiology and biogenesis, elucidating the precise mechanisms through which mitochondrial aberrations contribute to the onset and progression of renal fibrosis. We explored how mitochondrial dysfunction, mitochondrial cytopathy and mitochondrial autophagy mediate ECM deposition and renal fibrosis from a multicellular perspective of mesangial cells, endothelial cells, podocytes, macrophages and fibroblasts. Furthermore, it succinctly encapsulates the most recent advancements in the realm of mitochondrial-targeted therapeutic strategies aimed at mitigating renal fibrosis.

Poria acid (PAC) is a triterpene compound found in Poria cocos, a traditional Chinese medicine (TCM). The current study aims to explore the therapeutic effects and potential mechanisms of PAC on the migration and proliferation of human renal cell carcinoma (RCC) cells as well as tumor growth in animal model.

Cell viability and proliferative capacity of normal renal cells and RCC cells were investigated by MTT assay. In addition, 786-O cells were divided into four groups and treated with different concentrations of PAC (0, 20, 40, and 60 μM) for 48 h. Cell scratch test and cell invasion assay were performed to evaluate the effects of PAC on the invasion and migration of RCC cells, respectively. The effects of PAC on apoptosis of RCC cells and expression levels of PI3K/Akt/NF-kB signaling pathway-related biomarkers were investigated using TUNEL staining and Western blotting methods, respectively. Effects of PAC on the inhibitory activity of RCC tumor in mice were evaluated in a 786-O CDX model.

The study found that PAC inhibited the viability of RCC cells in a dose-dependent manner, as demonstrated by in vitro cell assays (p < 0.05). However, PAC showed no significant inhibitory effect on normal renal cells (p > 0.05). PAC also significantly inhibited the migration and invasion of RCC via EMT/MMP signaling pathways (p < 0.05). Immunofluorescence and immunoblotting results showed that PAC induced the apoptosis of RCC, which was accompanied by changes in the expression levels of apoptosis-related proteins (p < 0.05). Moreover, PAC significantly downregulated the PI3K/Akt/NF-kB signaling pathway in a concentration-dependent manner (p < 0.05). The effect of PAC on RCC apoptosis was dramatically reversed by 740Y-P (PI3K agonist) (p < 0.05) but significantly enhanced in the presence of LY294002 (PI3K inhibitor) (p < 0.05). The results of in vivo experiment also demonstrated that the antitumor activity of PAC was achieved by affecting the PI3K/Akt/NF-kB signaling pathway.

PAC can effectively suppress the proliferation, invasion and migration of RCC cells, and exhibit anti-tumor effects in RCC model by inhibiting the PI3K/Akt/NF-kB signaling pathway.

Chronic kidney disease (CKD) is a leading public health issue associated with high morbidity worldwide. However, there are only a few effective therapeutic strategies for CKD. Emodin, an anthraquinone compound from rhubarb, can inhibit fibrosis in tissues and cells. Our study aims to investigate the antifibrotic effect of emodin and the underlying molecular mechanism. A unilateral ureteral obstruction (UUO)-induced rat model was established to evaluate the effect of emodin on renal fibrosis development. Hematoxylin and eosin staining, Masson's trichrome staining, and immunohistochemistry staining were performed to analyze histopathological changes and fibrotic features after emodin treatment. Subsequently, a transforming growth factor-beta 1 (TGF-β1)-induced cell model was used to assess the inhibition of emodin on cell fibrosis in vitro. Furthermore, Western blot analysis and real-time quantitative reverse transcription-polymerase chain reaction were performed to validate the regulatory mechanism of emodin on renal fibrosis progression. As a result, emodin significantly improved histopathological abnormalities in rats with UUO. The expression of fibrosis biomarkers and mitochondrial biogenesis-related proteins also decreased after emodin treatment. Moreover, emodin blocked TGF-β1-induced fibrotic phenotype, lipid accumulation, and mitochondrial homeostasis in NRK-52E cells. Conversely, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) silencing significantly reversed these features in emodin-treated cells. Collectively, emodin plays an important role in regulating PGC-1α-mediated mitochondria function and energy homeostasis. This indicates that emodin exhibits great inhibition against renal fibrosis and acts as a promising inhibitor of CKD.

Renal fibrosis (RF) stands as a pivotal pathological process in the advanced stages of chronic kidney disease (CKD), and impeding its progression is paramount for delaying the advancement of CKD. The miR-10 family, inclusive of miR-10a and miR-10b, has been implicated in the development of various fibrotic diseases. Nevertheless, the precise role of miR-10 in the development of RF remains enigmatic. In this study, we utilized both an in vivo model involving unilateral ureteral obstruction (UUO) in mice and an in vitro model employing TGF-β1 stimulation in HK-2 cells to unravel the mechanism underlying the involvement of miR-10a/b in RF. The findings revealed heightened expression of miR-10a and miR-10b in the kidneys of UUO mice, accompanied by a substantial increase in p-Smad3 and renal fibrosis-related proteins. Conversely, the deletion of these two genes led to a notable reduction in p-Smad3 levels and the alleviation of RF in mouse kidneys. In the in vitro model of TGF-β1-stimulated HK-2 cells, the co-overexpression of miR-10a and miR-10b fostered the phosphorylation of Smad3 and RF, while the inhibition of miR-10a and miR-10b resulted in a decrease in p-Smad3 levels and RF. Further research revealed that miR-10a and miR-10b, through binding to the 3'UTR region of Vasohibin-1 (VASH-1), suppressed the expression of VASH-1, thereby promoting the elevation of p-Smad3 and exacerbating the progression of RF. The miR-10 family may play a pivotal role in RF.

Fibrosis, a pathological alteration of the repair response, involves continuous organ damage, scar formation, and eventual functional failure in various chronic inflammatory disorders. Unfortunately, clinical practice offers limited treatment strategies, leading to high mortality rates in chronic diseases. As part of investigations into gaseous mediators, or gasotransmitters, including nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), numerous studies have confirmed their beneficial roles in attenuating fibrosis. Their therapeutic mechanisms, which involve inhibiting oxidative stress, inflammation, apoptosis, and proliferation, have been increasingly elucidated. Additionally, novel gasotransmitters like hydrogen (H2) and sulfur dioxide (SO2) have emerged as promising options for fibrosis treatment. In this review, we primarily demonstrate and summarize the protective and therapeutic effects of gaseous mediators in the process of fibrosis, with a focus on elucidating the underlying molecular mechanisms involved in combating fibrosis.