Peritoneal dialysis (PD) can be used as renal replacement therapy when chronic kidney disease (CKD) progresses to end-stage renal disease. However, peritoneal fibrosis (PF) is a major cause of PD failure. Studies have demonstrated that PD fluid contains a significantly larger numbers of macrophages compared with the healthy individuals. During PD, macrophages can secrete cytokines to keep peritoneal tissue in sustained low-grade inflammation, and participate in the regulation of fibrosis-related signaling pathways, such as NF-κB, TGF-β/Smad, IL4/STAT6, and PI3K/AKT. A series of basic pathological changes occurs in peritoneal tissues, including epithelial mesenchymal transformation, overgeneration of neovasculature, and abnormal deposition of extracellular matrix. This review focuses on the role of macrophages in promoting PF during PD, summarizes the targets of macrophage-related inhibition of fibrosis, and provides new ideas for clinical research on delaying PF, maintaining the function and integrity of peritoneum, prolonging duration of PD as a renal replacement modality, and achieving longer survival in CKD patients.

Tanshinone IIA (Tan IIA), a bioactive compound derived from the traditional Chinese herb Salvia miltiorrhiza (Family Lamiaceae, Authority Bunge), is well-known for its protective effects in various kidney diseases. However, its role in obstructive nephropathy has not been thoroughly investigated.

This study aimed to explore the protective effects of Tan IIA in a mouse model of unilateral ureteral obstruction (UUO) and to elucidate the cellular and molecular mechanisms underlying these effects.

Gasdermin D (GSDMD) knockout mice and their wild-type (WT) littermates underwent UUO surgery, with Tan IIA treatment administered 24 h prior. Human proximal tubular cells (HK-2 cells) were treated with TGF-β1 to induce fibrosis (50 ng/mL for 24 h), followed by Tan IIA treatment (5 μM) for an additional 3 h.

Tan IIA significantly reduced the expression of extracellular matrix (ECM) components, including collagen I, α-smooth muscle actin (α-SMA), vimentin and fibronectin, in UUO mice. Tan IIA attenuated GSDMD-mediated pyroptosis. However, in GSDMD knockout mice subjected to UUO, the protective effects of Tan IIA on ECM gene expression and collagen deposition in the tubular interstitium were reduced. In vitro studies showed that Tan IIA reduced GSDMD activation and fibronectin protein expression in HK-2 cells.

Tan IIA may mitigate GSDMD-mediated pyroptosis in renal tubular epithelial cells (RTECs) and reduce kidney fibrosis, highlighting its potential as a therapeutic strategy to prevent the progression of kidney disease after ureteral obstruction.

To explore the optimal choice of seven diffusion models (DWI, IVIM, DKI, CTRW, FROC, SEM, and sADC) to assess renal interstitial fibrosis (IF) and annual renal function loss in chronic kidney disease (CKD).

One hundred thirty-three CKD patients and 30 controls underwent multi-b diffusion sequence scans. Patients were divided into the training, testing, and temporal external validation sets. Least absolute shrinkage and selection operator regression and logistic regression were used to select the optimal metrics for distinguishing the mild from moderate-to-severe IF. The performances of imaging, clinical, and combined models were compared. A linear mixed-effects model calculated estimated glomerular filtration rate (eGFR) slope, and multiple linear regression assessed the association between metrics and 1-3-year eGFR slopes.

The training, testing, and temporal external validation sets had 75, 30, and 28 patients, respectively. The combined model incorporating cortical fIVIM, MKDKI and eGFR was superior to the clinical model combining the eGFR and 24-hour urinary protein in all sets (net reclassification index [NRI] > 0, p < 0.05). Decision curve analysis showed the combined model provided greater net clinical benefit across most thresholds. Fifty-two, 35, and 16 patients completed 1-, 2-, and 3-year follow-ups. After adjusting for covariates, cortical fIVIM correlated with the 1-year eGFR slope (β = 30.600, p = 0.001), and cortical αSEM correlated with the 2- and 3-year eGFR slopes (β = 44.859, p = 0.002; β = 95.631, p = 0.019).

A combined model of cortical fIVIM, MKDKI and eGFR provides a useful comprehensive tool for grading IF, with cortical fIVIM and αSEM as potential biomarkers for CKD progression.

Ion channels, particularly those in the transient receptor potential (TRP) family, play key roles in cellular stress responses like inflammation and apoptosis, significantly impacting renal disease progression. Some channels such as TRPV1, TRPM2, TRPC6 impact renal pathology by mediating detrimental calcium influx, exacerbating oxidative stress, and promoting inflammatory pathways. Their activities are especially pronounced in conditions like ischemia and nephrotoxicity, common in acute kidney injury, and persist into chronic kidney injury, influencing fibrosis and nephron loss. Additionally, potassium and sodium channels like Kir4.1, KATP, and ENaC play critical roles in maintaining electrolyte balance and cellular energy under stress conditions. Further exploration of ion channel functionality and regulation is necessary to clarify their roles in renal disease. This review summarizes the involvement of ion channels in AKI and CKD and examines their potential clinical value in diagnosing and treating kidney disease.

Mesenchymal stem cell-derived exosomes (EXOs) represent a promising avenue for treating chronic kidney diseases (CKD), though their precise impact remains somewhat elusive. To address this gap, we conducted a systematic analysis, scouring databases and clinical trial repositories for relevant studies from 2019 to 2023. Seventeen papers were meticulously selected for their focus on mesenchymal stem cell-derived exosomes (MSC-EXOs) and their potential in CKD treatment. Our comprehensive meta-analysis, incorporating 15 preclinical and 6 clinical studies, underscores the efficacy of MSC-EXOs in improving renal function while attenuating tubular injury, inflammation, apoptosis, collagen deposition, and renal fibrosis. Notably, post-treatment with MSC-EXOs exhibited significant associations with various CKD markers, with pooled proportions indicating a considerable impact on blood urea nitrogen (BUN) and serum creatinine (SCR) levels. Subgroup analyses based on animal models further elucidated heterogeneity within the studies. In conclusion, MSC-EXOs demonstrate promise in enhancing renal function and reducing CKD risk, as evidenced by both preclinical and clinical data. Their efficacy in lowering SCR and BUN levels while enhancing filtration rate suggests MSC-EXOs as a viable and secure alternative to cell-based therapies, thereby providing valuable insights for personalized CKD treatments despite inherent limitations.

Chronic kidney disease (CKD) remains a significant global health burden, with hypertensive nephropathy (HN) as one of its primary causes. Podocyte injury is a key factor in the progression of CKD. However, the molecular mechanisms underlying angiotensin II-induced podocyte injury remain incompletely understood. Ubiquitin-specific protease 22 (USP22) has been reported to facilitate a range of cellular processes, including cell proliferation and apoptosis. However, the role of USP22 in HN pathogenesis is unclear.

The expression of USP22 was assessed in kidney samples from hypertensive nephropathy patients, angiotensin II-induced hypertensive nephropathy mouse models, and cultured podocytes treated with angiotensin II. Podocyte-specific USP22 knockout mice were used to investigate the effects of USP22 deletion on podocyte injury and inflammation.

USP22 expression was significantly upregulated in kidneys of HN patients, angiotensin II-induced mouse models, and cultured podocytes. Podocyte-specific deletion of USP22 markedly reduced angiotensin II-induced podocyte injury and inflammatory responses. Furthermore, we identified high-mobility group box protein 1 (HMGB1) as a protein that interacts with USP22. USP22 deubiquitinated and stabilized HMGB1 through K48-linked ubiquitination. Downregulation of USP22 expression improved kidney function and pathological changes in HN by promoting HMGB1 degradation.

This study identifies USP22 as a key regulator of angiotensin II-induced podocyte injury and inflammation through its interaction with HMGB1. Our findings revealed that following glomerular injury, damage and shedding of tubular cells also occurred. Targeting the USP22-HMGB1 axis offers a promising therapeutic strategy for treating hypertensive nephropathy and other types of CKD.

Ischemia-reperfusion injury (IRI) is the primary cause of acute kidney injury (AKI), which can result in chronic kidney disease (CKD) with renal fibrosis. Magnesium lithospermate B (Mlb), a bioactive compound produced from Salvia miltiorrhiza Bunge, exerts nephroprotective effects against AKI. However, the significance of Mlb in the evolution of IRI-induced AKI in patients with CKD remains unclear. Notably, the specific mechanisms underlying the putative antifibrotic activities of Mlb during this progression remain to be fully elucidated.

This study sought to explore the therapeutic benefits of Mlb in AKI-to-CKD progression and uncover the potential mechanisms, with a special interest in its effects on renal fibrosis and cell cycle regulation.

Unilateral ischemia/reperfusion (UIR)-induced mouse AKI-to-CKD progression (in vivo) and HK-2 cells with TGF-β-induced fibrosis model (in vitro) were used in the study. The beneficial effects of Mlb on renal fibrosis and cell cycle-related signaling pathways were investigated using histological analysis, molecular assays, network pharmacology, and RNA sequencing.

Mlb treatment significantly reduced renal dysfunction, inflammation, apoptosis, and the G2/M phase cell cycle stalling in mice 14 days post-UIR-induced AKI, subsequently improving renal fibrosis. Mechanistically, Mlb promotes the activity of the CDK1/Cyclin B1 signaling pathway, thereby alleviating the G2/M phase cell cycle stalling. Network pharmacology and RNA sequencing analyses identified the KLF5/CDK1/Cyclin B1 signaling pathway as a potential target of the antifibrotic effects of Mlb, which was further verified in both in vivo and in vitro experiments. The KLF5 inhibitor ML264 attenuated the protective effects of Mlb by reducing CDK1/Cyclin B1 expression and reinstating the G2/M phase cell cycle stalling, highlighting the critical role of this pathway in Mlb-mediated renal protection.

Mlb decreases renal fibrosis by inhibiting the G2/M phase cell cycle stalling via the KLF5/CDK1/Cyclin B1 signaling pathway during AKI-to-CKD progression. Our findings offer new insight into the therapeutic potential of Mlb in preventing CKD progression following AKI and identify a previously unrecognized mechanism involving the KLF5/CDK1/Cyclin B1 pathway.

To develop and validate an ultrasomics-based machine-learning (ML) model for non-invasive assessment of interstitial fibrosis and tubular atrophy (IF/TA) in patients with IgA nephropathy (IgAN).

In this multi-center retrospective study, 471 patients with primary IgA nephropathy from four institutions were included (training, n = 275; internal testing, n = 69; external testing, n = 127; respectively). The least absolute shrinkage and selection operator logistic regression with tenfold cross-validation was used to identify the most relevant features. The ML models were constructed based on ultrasomics. The Shapley Additive Explanation (SHAP) was used to explore the interpretability of the models. Logistic regression analysis was employed to combine ultrasomics, clinical data, and ultrasound imaging characteristics, creating a comprehensive model. A receiver operating characteristic curve, calibration, decision curve, and clinical impact curve were used to evaluate prediction performance.

To differentiate between mild and moderate-to-severe IF/TA, three prediction models were developed: the Rad_SVM_Model, Clinic_LR_Model, and Rad_Clinic_Model. The area under curves of these three models were 0.861, 0.884, and 0.913 in the training cohort, and 0.760, 0.860, and 0.894 in the internal validation cohort, as well as 0.794, 0.865, and 0.904 in the external validation cohort. SHAP identified the contribution of radiomics features. Difference analysis showed that there were significant differences between radiomics features and fibrosis. The comprehensive model was superior to that of individual indicators and performed well.

We developed and validated a model that combined ultrasomics, clinical data, and clinical ultrasonic characteristics based on ML to assess the extent of fibrosis in IgAN.

Question Currently, there is a lack of a comprehensive ultrasomics-based machine-learning model for non-invasive assessment of the extent of Immunoglobulin A nephropathy (IgAN) fibrosis. Findings We have developed and validated a robust and interpretable machine-learning model based on ultrasomics for assessing the degree of fibrosis in IgAN. Clinical relevance The machine-learning model developed in this study has significant interpretable clinical relevance. The ultrasomics-based comprehensive model had the potential for non-invasive assessment of fibrosis in IgAN, which helped evaluate disease progress.

Obstructive nephropathy is a leading cause of kidney injury and fibrosis, which is always associated with metabolic aberrations and chronic inflammation. Succinate is an important intermediate metabolite involved in inflammatory responses and various diseases. However, the precise pathogenic mechanisms of succinate in obstructive nephropathy remain to be elucidated.

Succinate was supplemented in the drinking water to study its impact on the pathogenesis of obstructive nephropathy induced by unilateral ureteral obstruction (UUO) in mice. Kidney fibrosis, injury, inflammatory cytokines, and infiltrated immune cells were analyzed. Transcriptome analysis and in vitro studies were performed to study the cellular and molecular mechanisms by which succinate regulates CD4+ T cells and renal fibrosis.

Kidney proteomics revealed that the tricarboxylic acid (TCA) cycle and mitochondrial dysfunction were the hallmarks of obstructive nephropathy. Succinate was significantly accumulated in the obstructed kidneys. Succinate supplementation promoted UUO-induced renal fibrosis, injury, and inflammation. Moreover, succinate facilitated renal infiltration of CD4+ T cells by upregulating the T-cell chemokines CXCL9 and CXCL10. Transcriptome analysis suggested that succinate promoted CD4+ T cell activation and induced the production of CCL1, which mediated the transition of fibroblasts to myofibroblasts through the ERK signaling pathway. Recombinant CCL1 treatment promoted UUO-induced renal fibrosis and inflammation.

Our study uncovers the important role of succinate in mediating T-cell response that orchestrates the pathogenesis of obstructive nephropathy. Targeting succinate accumulation may be a therapeutic strategy for the treatment of obstructive nephropathy.

Kidney disease (KD) has gradually become a major social and economic burden on the healthcare system. Recent studies highlight ferroptosis as a critical mechanism in the progression of these conditions. Recognized for its essential role in renal pathogenesis, ferroptosis is attracting increasing research attention and emerging as a key focus of investigation. The Nrf2 signaling pathway, known for its regulatory influence on ferroptosis, plays a central role in this context. Activation of the nuclear factor E2-related factor 2 (Nrf2) pathway and the subsequent attenuation of ferroptosis present substantial opportunities as novel therapeutic targets for managing kidney injury (KI). This article summarizes the latest mechanism of action of the Nrf2 pathway in ferroptosis, explores how the Nrf2 pathway affects ferroptosis in KD therapy, and investigates the potential therapeutic effects of natural products targeting the Nrf2 pathway. These natural products have been shown to inhibit ferroptosis through the Nrf2 pathway, providing new insights and therapeutic strategies for the clinical and individualized management of KD.

Polycystic ovary syndrome (PCOS) represents the most prevalent endocrine disorder among women of reproductive age, affecting approximately 5-18% of females worldwide. Characterized by irregular ovulation, hyperandrogenism, and polycystic ovaries, hyperandrogenism is the defining feature. Recent evidence highlights that, in addition to its notable reproductive and metabolic consequences, PCOS may also contribute to an elevated risk of renal complications. This increased risk is attributed to chronic low-grade inflammation, hormonal dysregulation, and disturbances in lipid metabolism inherent to the condition. However, the pathological mechanisms, clinical manifestations, and progression of secondary renal damage in this cohort remain insufficiently studied. This review consolidates current understanding of the relationship between PCOS and chronic kidney disease (CKD), aiming to clarify potential mechanisms by which PCOS may induce secondary renal dysfunction, encompassing both direct renal impairment and indirect damage mediated through systemic alterations. Furthermore, it advocates for comprehensive management strategies to mitigate renal risks in patients with PCOS, emphasizing the necessity of multidisciplinary approaches and further research to address these critical gaps.

Hereditary transthyretin amyloidosis (ATTRv) is a fatal disease that affects multiple organs. Up to 30% of patients with ATTRv also experience renal complications, including proteinuria and a decline in eGFR. Recently, new treatments for ATTRv, a tetramer stabiliser and transthyretin small interfering RNA (TTR siRNA) therapeutics, have emerged. However, the effectiveness of these new treatments on renal complications in ATTRv remains unknown.

We retrospectively collected clinical data from ATTRv patients and analysed the relationship between the initial renal complications and age. We also examined whether the new treatments affected the clinical course of renal symptoms, using eGFR changes or longitudinal data on urine protein/albumin creatinine ratio.

A total of 16 patients' data were collected. Regarding their initial renal complications, we found that patients with proteinuria had an earlier age at onset than those with a decline in eGFR. Notably, longitudinal data showed that TTR siRNA therapeutics reduced proteinuria and increased serum protein, while none of the new treatments could demonstrate a significant improvement in the slope of eGFR decline.

We demonstrated that TTR siRNA therapeutics represent potential candidates for ATTRv nephropathy, despite the fact that their use has been limited to neurological symptoms to date.

Studies concerning the effect of co-exposure to melamine and phthalates on kidney function in children are rare. Thus, this study examines the above-mentioned relationship and their sex-different effect. Whether the exposure of the two chemicals from their mothers, when children were in the womb during the third trimester, affected renal injury markers in children afterwards is also examined. This study was from Taiwan Maternal and Infant Cohort Study cohort established in October 2012 to enroll third-trimester pregnant mothers up to May 2015. Their offspring were subsequently recruited between 2016 and 2020 as our study children. One-spot urine specimens were collected from both pregnant mothers (2012-2015) and study children (2016-2020) for the simultaneous measurement of melamine and 11 phthalate metabolites. Daily intakes of melamine and five phthalates, including DEHP (di-2-ethylhexylphthalate), DiBP (Dibutyl phthalate), DnBP (Di-n-butyl phthalate), BBzP (Butyl benzyl phthalate), and DEP (Diethyl phthalate), were estimated using a creatinine excretion-based model in both study children and their mothers. Two early markers of renal injury, microalbumin and N-acetyl-beta-D-glucosaminidas (NAG), were measured in urine samples of study children (2016-2020). A total of 552 eligible children were studied, with a mean age of 4 years. We found that boys in the highest quartile of estimated melamine intake (≥0.68 μg/kg/day) had significantly higher urine ACR levels and in the highest quartile of estimated phthalate intake of DEHP (≥5.36 μg/kg/day), DEP (≥0.89 μg/kg/day), and DiBP (≥1.19 μg/kg/day) had significantly higher urine NAG levels when compared to the combined three lowest quartile ones as comparison groups. No significant associations were found between their mothers' phthalates and melamine intake during the third trimester and urine ACR and NAG in children. We conclude that children (particularly boys) with high co-exposure of melamine and certain phthalate chemicals among children have increased early markers of kidney injury.

Renal fibrosis is a critical pathological characteristic of chronic kidney disease, and current antifibrotic therapies has limited efficacy. Sodium butyrate (NaB) has been shown to be highly effective in mitigating bleomycin-induced pulmonary fibrosis; however, its specific impact on renal fibrosis and the underlying mechanisms remain unclear. This study aims to elucidate the role and mechanism of NaB in renal fibrosis by using a mouse model of renal fibrosis induced through Unilateral Ureteral Obstruction (UUO) and folic acid (FA) administration.

NaB significantly decreased the distribution of collagen fibers in renal tissues and mitigated fibrosis in a dose-dependent manner. Further analysis indicated that NaB inhibited M2 macrophage polarization in the renal tissues of UUO model mice by blocking the phosphorylation of STAT6, hence reducing renal fibrosis. Additionally, in vitro experiments demonstrated that NaB inhibited fibroblast activation induced by M2 macrophages. Mechanistic studies revealed that NaB attenuates fibroblast activation and M2 macrophage polarization by upregulating LKB1 and inhibiting the activation of the STAT6 signaling pathway.

NaB may exert its effects by inhibiting the activation of the IL-4/STAT6 signaling pathway through the upregulation of LKB1, which suppress the polarization of M2 macrophages and consequently reduce renal fibrosis. These findings establish a theoretical foundation for NaB as a novel drug candidate for renal fibrosis and indicate its potential applicability in clinical treatments for this condition.

The protein lysine methyltransferase 2 (SMYD2) can affect cell proliferation, differentiation, and survival through methylation of its histone and non-histone substrates. SMYD2 has been shown to act as an oncogene to promote disease progression in a variety of cancer diseases, but its role in chronic kidney diseases (CKD) pathogenesis has not been fully elucidated. This study aims to investigate the effect of SMYD2 on cisplatin-induced CKD and its underlying mechanisms. In this study, we found that cisplatin caused severe renal injury in mice, which was accompanied by the up-regulation of SMYD2 expression. AZ505 treatment significantly down-regulated cisplatin-induced renal injury and fibrosis. It also alleviated renal apoptosis and inhibited the phosphorylation level of NF-κB p65. Conditional knockdown of Smyd2 achieved similar effects as AZ505. In renal tubular epithelial cells, inhibition or silencing of SMYD2 down-regulated cisplatin-induced apoptotic response, while overexpression of SMYD2 induced apoptotic response and activated NF-κB in response to the up-regulation of SMYD2 expression. Up-regulation of SMYD2 induced interaction and phosphorylation of SMYD2 and NF-κB p65, and inhibition of NF-κB activation further suppressed cisplatin-induced NF-κB activation and apoptosis. The present study suggests that up-regulation of SMYD2 expression in cisplatin-induced CKD may promote apoptosis of renal tubular epithelial cells and accelerate the process of renal injury through NF-κB activation. SMYD2 may serve as a potential target for effective CKD treatment.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. Despite advancements in various treatments, the prevalence of DKD continues to rise, leading to a significant increase in the demand for dialysis and kidney transplantation. This study aimed to evaluate the effects of a Small cell＋Ultra Potent＋Scale UP cell (SMUP-Cell), a type of human umbilical cord blood-derived mesenchymal stem cell, on DKD in the db/db mouse model of type 2 diabetes mellitus. After administering SMUP-Cells via tail vein injection in db/db mice, the animals were monitored over a three-month period. The db/db mice exhibited an increased urine albumin-to-creatinine ratio (UACR). However, the administration of SMUP-Cells resulted in a reduction of the UACR. The expression levels of desmin, α-smooth muscle actin, and fibronectin-markers of epithelial-mesenchymal transition (EMT)-as well as kidney injury molecule 1, a sensitive marker of tubular injury, were significantly elevated in db/db mice. Treatment with SMUP-Cells ameliorated all of these changes. Notably, Gremlin isoform 2 (Grem2) exhibited the most significant difference in expression according to the transcriptome analysis. The elevated expression of Grem2 in db/db mice was significantly reduced following SMUP-Cell treatment. In vitro, treatment with high glucose and cholesterol induced Grem2 expression in renal tubular epithelial cells (RTECs), while Grem2 knockdown effectively prevented fibrosis and senescence induced by high glucose and cholesterol in RTECs. These observations suggest that SMUP-Cells inhibit the progression of DKD by inhibiting EMT through the reduction of Grem2 expression in RTECs.

In chronic kidney disease (CKD) research, animal models such as the unilateral ureteral obstruction (UUO) rodent model are crucial to understanding disease progression, particularly renal fibrosis. Despite its widespread use, the molecular mechanisms driving CKD remain incompletely understood. Given the interplay between metabolism and fibrosis, a comprehensive metabolomic analysis of UUO renal tissue is necessary. This study involved untargeted multiplatform analysis using liquid chromatography (LC), gas chromatography (GC), and capillary electrophoresis (CE) coupled with mass spectrometry (MS) to examine murine kidney tissue from the UUO model. The results highlight metabolic changes associated with tubulointerstitial fibrosis, which affect pathways such as the tricarboxylic acid (TCA) cycle, the urea cycle, and lipid metabolism. In particular, fibrosis impacts the lipidomic profile, with decreases in most lipid classes and increases in specific glycerophospholipids, hexosylceramides, and cholesterol esters. These findings demonstrate the value of a multiplatform approach in elucidating metabolic alterations in CKD, providing information on the underlying molecular mechanisms and paving the way for further research.

Cellular communication network factor 2 (CCN2, also known as CTGF) is a complex protein that regulates numerous cellular functions. This biomolecule exhibits dual functions, depending on the context, and can act as a matricellular protein or as a growth factor. CCN2 is an established marker of fibrosis and a well-known mediator of kidney damage, involved in the regulation of inflammation, extracellular matrix remodeling, cell death, and activation of tubular epithelial cell (TECs) senescence. In response to kidney damage, cellular senescence mechanisms are activated, linked to regeneration failure and progression to fibrosis. Our preclinical studies using a total conditional CCN2 knockout mouse demonstrate that CCN2 plays a significant role in the development of a senescence phenotype after exposure to a nephrotoxic agent. CCN2 induces cell growth arrest in TECs, both in the early phase and in the chronic phase of folic acid nephropathy (FAN), associated with cell-death/necroinflammation and fibrosis, respectively. Renal CCN2 overexpression was found to be linked to excessive collagen accumulation in tubulointerstitial areas, microvascular rarefaction, and a decline in renal function, which were observed three weeks following the initial injury. All these findings were markedly diminished in conditional CCN2 knockout mice. In the FAN model, injured senescent TECs are associated with microvascular rarefaction, and both were modulated by CCN2. In primary cultured endothelial cells, as previously described in TECs, CCN2 directly induced senescence. The findings collectively demonstrate the complexity of CCN2, highlight the pivotal role of cellular senescence as an important mechanism in renal injury, and underscore the critical function of this biomolecule in kidney damage progression.

Objective: Emerging evidence suggests that diet modulates gut microbiota, which in turn influences chronic kidney disease (CKD) progression. This study investigates the association between the newly proposed Dietary Index for Gut Microbiota (DI-GM) and the prevalence and prognosis of CKD. Methods: This cross-sectional study analyzed data from the U.S. National Health and Nutrition Examination Survey 2007-2020. DI-GM scores were calculated based on dietary intake of 14 food components, categorized as beneficial or unfavorable. Weighted linear regression model, logistic regression model, and restricted cubic spline analysis were used to assess the associations of DI-GM with CKD. Results: The prevalence of CKD among 28,512 participants was 17.4 %. Higher DI-GM was negatively associated with CKD prevalence (OR = 0.967, 95 %CI: 0.939-0.995, p = 0.026) and with very high-risk prognosis (OR = 0.877, 95 %CI: 0.821-0.937, p < 0.001). Beneficial DI-GM components were significantly associated with lower CKD risk (OR = 0.928, 95 %CI: 0.892-0.966, p < 0.001), while no significant association was observed for unfavorable components. Higher DI-GM and beneficial DI-GM levels were linearly associated with improved CKD prognosis (p for trend <0.001). Coffee and fiber were primary contributors to both the prevalence and prognosis of CKD, while whole grains primarily impacted its prognosis. Conclusions: Higher DI-GM, driven by beneficial dietary components, is associated with reduced CKD prevalence and improved prognosis. These findings suggest that promoting beneficial dietary patterns to enhance gut microbiota may play a pivotal role in CKD management.

Chronic kidney disease (CKD) is a major global health burden that affects more than 10% of the adult population. Current treatments, including dialysis and transplantation, are costly and not curative. Kidney fibrosis, defined as an abnormal accumulation of extracellular matrix in the kidney parenchyma, is a common outcome in CKD, regardless of disease aetiology, and is a major cause of loss of kidney function and kidney failure. For this reason, research efforts have focused on identifying mediators of kidney fibrosis to inform the development of effective anti-fibrotic treatments. Given the prominent role of the transforming growth factor-β (TGFβ) family in fibrosis, efforts have focused on inhibiting TGFβ signalling. Despite hopes raised by the efficacy of this approach in preclinical models, translation into clinical practice has not met expectations. Antihypertensive and antidiabetic drugs slow the decline in kidney function and could slow fibrosis but, owing to the lack of technologies for in vivo renal imaging, their anti-fibrotic effect cannot be truly assessed at present. The emergence of new drugs targeting pro-fibrotic signalling, or enabling cell repair and cell metabolic reprogramming, combined with better stratification of people with CKD and the arrival of nanotechnologies for kidney-specific drug delivery, open up new perspectives for the treatment of this major public health challenge.

The limited evidence reports the relationship between plasma dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP) and Diabetic kidney disease (DKD) in patients with Type 2 Diabetes Mellitus (T2DM). Therefore, the present study aimed to evaluate the diagnostic potential of dp-ucMGP in DKD among T2DM patients.

This cross-sectional study was conducted from December 2023 to January 2025, including 75 T2DM patients. Participants were classified into three groups based on urinary albumin-to-creatinine ratio (UACR): Normoalbuminuria, microalbuminuria, and macroalbuminuria with n = 25 in each group. Pearson correlation analysis was performed to assess the relationship between dp-ucMGP and other biochemical parameters. Receiver Operating Characteristic (ROC) curve analysis was used to evaluate the diagnostic potential of dp-ucMGP for early detection of DKD. A p value < 0.05 was considered statistically significant.

The plasma dp-ucMGP levels were significantly higher in T2DM patients in the macroalbuminuria group, with a mean of 1069.86 ± 417.56 pmol/L, followed by the microalbuminuria (842.72 ± 342.02 pmol/L) and normoalbuminuria (586.38 ± 336.15 pmol/L) groups. Similarly, higher dp-ucMGP levels were observed in patients with DKD severity stage IV (1401.53 ± 401.49 pmol/L). A negative correlation with eGFR (r = -0.807, p < 0.0001) and a positive correlation with age, serum creatinine, UACR, blood urea, uric acid and triglycerides were observed. The area under the curve (AUC) was 0.913 (95% CI: 0.820-0.960; p < 0.0001) for dp-ucMGP.

In conclusion, our findings revealed that plasma dp-ucMGP could be a potential biomarker to predict the early detection of DKD in patients with T2DM.

To develop an interpretable deep learning (XDL) model based on superb microvascular imaging (SMI) for the noninvasive diagnosis of the degree of interstitial fibrosis (IF) in chronic kidney disease (CKD).

We included CKD patients who underwent renal biopsy, two-dimensional ultrasound, and SMI examinations between May 2022 and October 2023. Based on the pathological IF score, they were divided into two groups: minimal-mild IF (≤25%) and moderate-severe IF (>25%). An XDL model based on the SMI while establishing an ultrasound radiomics model and a color doppler ultrasonography (CDUS) model as the control group. The utility of the proposed model was evaluated using the receiver operating characteristic curve (ROC) and decision curve analysis.

In total, 365 CKD patients were included herein. In the validation group, AUCs of the ROC curves for the DL, ultrasound radiomics, and CDUS models were 0.854, 0.784, and 0.745, respectively. In the test group, AUCs of the ROC curve for the DL ultrasound radiomics, and CDUS models were 0.824, 0.792, and 0.752, respectively. The pie chart and heat map based on Shapley additive explanations (SHAP) provided substantial interpretability for the model.

Compared with the ultrasound radiomics and CDUS models, the DL model based on the SMI had higher accuracy in the noninvasive judgment of the degree of IF in CKD patients. Pie and heat maps based on Shapley can explain which image regions are helpful in diagnosing the degree of IF.

An investigation of the mangrove-derived fungus Penicillium sp. DM27 led to the isolation of 19 new compounds, including three pairs of piperidinone enantiomers ( ±)-1, ( ±)-2, and ( ±)-3, two pairs of pyrrolidinone enantiomers ( ±)-4 and ( ±)-5, and nine pyrrolidine derivatives 6-14. The structures of 1-14 were elucidated through NMR and HRESIMS analysis, coupled with experimental and calculated ECD spectroscopy and the modified Mosher method. Quantitative real time PCR and Western bolt analyses revealed that 11 blocked EMT in TGF-β1-treated HK-2 cells and suppressed fibroblast activation in TGF-β1-stimulated NIH-3T3 cells. Molecular simulations demonstrated that compound 11 could dock ADAM17, showing a high negative binding affinity. Additionally, the overexpression of ADAM17 by lentiviral infection triggered renal tubular EMT, while compound 11 suppressed this process. Overall, our research suggests that pyrrolidine derivatives may be potential therapeutic agents for the treatment of fibrotic kidney disease.

The online version contains supplementary material available at 10.1007/s42995-025-00282-0.

Renal fibrosis is a hallmark of chronic kidney disease (CKD). In traditional Chinese medicine, Rubus chingii Hu (raspberry) is believed to have kidney-tonifying properties. However, whether raspberry can effectively treat CKD, along with the specific active compounds and underlying mechanisms, remains unclear.

This study aims to investigate the potential of raspberries in treating CKD and elucidate the mechanisms involved.

CKD model was established in rats using adenine. The effects of raspberry treatment on CKD were assessed through macroscopic observations and pathological changes in the kidney. The expression of fibrotic proteins in renal tissues was analyzed to evaluate the impact of raspberry on renal fibrosis. Data mining combined with compositional analysis were employed to identify the active ingredients, targets, and pathways of raspberry that may improve CKD. Subsequently, Western blotting and immunofluorescence analysis were conducted to confirm the involvement of the PI3K/AKT signaling pathway in the renoprotective mechanism of raspberry.

Raspberry treatment significantly alleviated renal pathological damage, fibrosis and inflammation in model rats, showing effects comparable to irbesartan (Avapro). Chemical composition analysis and network pharmacology predicted AKT1 as the core target, and the PI3K/AKT pathway plays a pivotal role in mediating the therapeutic effects of raspberry extract in CKD. Molecular docking studies further confirmed that active compounds in raspberry have a strong binding affinity with AKT1. Western blotting and immunofluorescence results demonstrated that raspberry inhibited phosphorylation, thereby suppressing the PI3K/AKT pathway, leading to its antifibrotic effect on the kidney.

Raspberry was firstly discovered to potentially treat CKD by alleviating renal fibrosis through inhibition of the PI3K/AKT pathway. Raspberry, as a medicinal and edible traditional herb, could serve as a promising therapeutic agent or health supplement for improving renal fibrosis and slowing CKD progression.

The incidence and hospitalization rate of kidney disease, especially end-stage renal disease, have increased significantly, which seriously endangers the health of patients. Mitochondria are the core organelles of cellular energy metabolism, and their dysfunction can lead to kidney energy supply insufficiency and oxidative stress damage, which has become a global public health problem. Studies have shown that the disturbance of mitochondrial quality control mechanisms, including mitochondrial dynamics, autophagy, oxidative stress regulation and biosynthesis, is closely related to the occurrence and development of renal fibrosis (RF). As a multicellular pathological process, RF involves the injury and shedding of podocytes, the transdifferentiation of renal tubular epithelial cells, the activation of fibroblasts, and the infiltration of macrophages, among which the mitochondrial dysfunction plays an important role. This review systematically elaborates the molecular mechanisms of mitochondrial damage during RF progression, aiming to provide theoretical foundations for developing novel therapeutic strategies to delay RF advancement.

Renal fibrosis, a key progression of chronic kidney disease (CKD), remains a major challenge in nephrology, with no FDA-approved drugs specifically targeting this condition. Interleukin-11 (IL-11) has emerged as a potential therapeutic target for renal fibrosis. In this study, we identified the antifibrotic effects of a recombinant human IL-11 analogue, IL-11-6M, in a mouse model of unilateral ureteral obstruction (UUO). We generated additional IL-11-6M variants via an optimized Escherichia coli expression system, with one variant (D46C) exhibiting comparable efficacy. Further modified through cysteine-specific PEGylation, analogue 13 demonstrated similar potency to IL-11-6M with an IC50 value of 61.5 ± 26.2 nM and maintained strong binding affinity to IL-11Rα (KD = 3.0 nM). Notably, analogue 13 exhibited a prolonged half-life and showed significant therapeutic effects in the UUO-induced renal fibrosis model. These findings suggest analogue 13 should be a promising candidate for the treatment of renal fibrosis.

Research indicates that minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) may reflect varying severities of the same underlying condition, with inflammation potentially facilitating the progression from MCD to FSGS. The aim of this study was to determine the whether systemic inflammation accelerated the progression from MCD to FSGS in a mouse model of Adriamycin-induced nephrosis. In this model, systemic inflammation induced transient proteinuria without significant serum biochemical alterations or significant renal histological changes in control mice that did not develop nephrotic syndrome. In contrast, both mice with Adriamycin-induced nephrosis mice and mice with Adriamycin-induced nephrosis with systemic inflammation showed histological features of MCD at week 4 and progressive exacerbation of FSGS. However, the glomerular lesions of mice with Adriamycin-induced nephrosis in a state of systemic inflammation were more obvious than those of mice with Adriamycin-induced nephrosis. These findings suggest that systemic inflammation may hasten histological development from MCD to FSGS in this mouse model.

Renal fibrosis, resulting from myofibroblast-mediated excessive extracellular matrix (ECM) deposition, lacks effective treatments. Novel peptide DR3penA developed by our group showed therapeutic potential for fibrotic diseases; however, its application was hindered by poor stability and bioavailability. To address this unmet need, we implemented stepwise optimization of DR3penA. The conformationally restricted analogs designed via structural predictions enhanced both activity and stability. Through structure-activity relationship analysis and cleavage site mapping, introducing unnatural amino acids improved stability. Fatty acid modifications conferred fibroblast-selective cytotoxicity and improved pharmacokinetics. After several rounds of progressive modification, peptide 27 exhibited remarkable stability, with a 5.68-fold extended half-life compared to DR3penA. Following profibrotic stimuli, peptide 27 effectively inhibited myofibroblast activation, epithelial-mesenchymal transition, and ECM synthesis. It also attenuated renal fibrosis in a unilateral ureteral obstruction model. Our study leverages multiple modifications that integrate cell and animal models to identify peptide 27 as a promising candidate for renal fibrosis therapy.

Chronic kidney disease (CKD) is creating an ever heavier global health burden with population ageing. This study aimed to examine the longitudinal associations of remnant cholesterol (RC) with CKD morbidity in a large high-risk population (type 2 diabetes and hypertension).

A total of 11,881 participants who participated in annual health examinations from 2021 to 2023 were included in our analysis. The Cox proportional hazards model was performed to analyze the associations of baseline RC, cumulative RC, and variability of RC with CKD morbidity. The cross-lagged panel analysis was used to examine the temporal relationship between RC and renal function.

The results of the multivariable-adjusted models showed that higher baseline, cumulative RC, and variability of RC were related to higher risks of developing CKD, the adjusted HR (95% CI) comparing tertile 3 with tertile 1 were 1.26 (95% CI 1.10-1.45), 1.33 (95% CI 1.16-1.52), 1.36 (95% CI 1.20-1.55), respectively. Stratified analysis found that gender did not change these associations. Compared with individuals in the low cumulative and variability RC group, those in the high cumulative and variability RC group had a 1.62 times higher risk of CKD (95% CI: 1.34-1.96). The cross-lagged panel analysis showed that the increase in RC levels may precede the decrease in eGFR.

High baseline level, cumulative exposure to RC, and variability of RC are associated with increased CKD risk. Therefore, monitoring RC-related parameters is crucial to delay the occurrence and development of CKD in high-risk populations.

High urea can induce depression and anxiety. Activation of astrocytes is closely associated with psychiatric disorders. However, the pathological mechanism of whether high urea affects astrocyte structure and function to induce anxiety-like behaviors remain unclear. We established a high-urea chronic kidney disease (CKD) mouse model and found that these mice exhibited elevated levels of anxiety through behavioral experiments. Immunofluorescence and transmission electron microscopy studies of astrocytes revealed a decrease in density and branching of mPFC astrocytes. Additionally, we observed a significant reduction in ATP and BDNF levels in the mPFC and primary astrocytes of CKD mice induced by high urea. Analysis of gene expression differences in astrocytes between WT and high-urea mice indicated alterations in mitochondrial dynamics-related signaling pathways in astrocytes. We established a high-urea primary astrocyte model to assess mitochondrial function and levels of fusion and fission proteins. Treatment of primary astrocytes with high urea led to mitochondrial fragmentation and downregulation of Mfn2 expression. These results suggested that high urea downregulates Mfn2 expression in mPFC astrocytes, induced mitochondrial fusion-fission abnormalities, disrupted astrocyte energy metabolism, and promoted high-urea-related anxiety. Mfn2 may represent a potential therapeutic target for high-urea-related anxiety.

Chronic inflammatory diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), atherosclerosis, and inflammatory bowel disease (IBD), pose major global health concerns. These disorders are marked by persistent inflammation, immune system dysfunction, tissue injury, and fibrosis, ultimately leading to severe organ dysfunction and diminished quality of life. Osteopontin (OPN), a multifunctional extracellular matrix protein, plays a crucial role in immune regulation, inflammation, and tissue remodeling. It promotes immune cell recruitment, stimulates pro-inflammatory cytokine production, and contributes to fibrosis through interactions with integrins and CD44 receptors. Additionally, OPN activates key inflammatory pathways, including NF-κB, MAPK, and PI3K/Akt, further aggravating tissue damage in chronic inflammatory conditions. Our review highlights the role of OPN in chronic inflammation, its potential as a biomarker, and its therapeutic implications. We explore promising preclinical approaches, such as monoclonal antibodies, small molecule inhibitors, and natural compounds like curcumin, which have demonstrated potential in mitigating OPN-driven inflammation. However, challenges persist in selectively targeting OPN while maintaining its essential physiological roles, including bone remodeling and wound healing. Our review offers insights into therapeutic strategies and future research directions.

Bicyclol, a drug stemmed from the traditional Chinese medicine Schisandra chinensis, has been widely utilized in clinical practice due to its efficacy and safety to manage hepatopathy. Its diverse biological properties-including antiviral, anti-inflammatory, antifibrotic, immunomodulatory, antioxidative, antisteatotic, and antitumor effects-underscore its significant medicinal effects in versatile hepatic disorders, incorporating viral hepatitis, non-alcoholic fatty liver disease, hepatocellular carcinoma, acute hepatic failure, hepatic fibrosis as well as drug-induced liver injury. Furthermore, ongoing researches into the molecular mechanisms, biological activities and mode of actions concerning bicyclol have uncovered its potential therapeutic implications in other multiple diseases/conditions. Studies have indicated promising efficacy pertaining to bicyclol to treat idiopathic pulmonary fibrosis, acute lung injury, cerebral ischemia/reperfusion injury, renal dysfunction, renal cell carcinoma, and cardiovascular diseases. Accordingly, this narrative review article summarizes the current understanding of diverse biological activities and underpinning mechanisms of bicyclol across a range of diseases, as well as its pharmacokinetics, toxicity profile and shed light on future perspectives.

Renal fibrosis represents the final common pathological manifestation of chronic kidney disease (CKD), yet the underlying mechanism remains elusive, and there is still a lack of effective targeted therapeutic strategy. Although previous research indicated that repressor element 1-silencing transcription factor (REST) contributed to acute kidney injury (AKI) in renal tubular epithelial cells (RTECs), its specific contribution to renal fibrosis and associated mechanisms remains largely unexplored.

Renal biopsies from CKD patients were collected to evaluate the expression of REST. Kidney-specific Rest conditional knockout (Cdh16-Cre/Restflox/flox) mice were generated and employed unilateral ureter obstruction (UUO) models to investigate the role of REST in renal fibrosis. RNA sequencing was performed to elucidate the mechanism. Mitochondrial function was evaluated by transmission electron microscopy (TEM), reactive oxygen species (ROS), oxygen consumption rates (OCR), extracellular acidifcation rate (ECAR) and adenosine triphosphate (ATP). The severity of renal fibrosis was assessed through Western blot, immunofluorescent staining and immumohistochemical staining. Bioinformatic prediction, dual luciferase reporter gene assay, point mutation and chromatin immunoprecipitation (ChIP) assay were utilized to clarify the molecular mechanism.

REST was significantly up-regulated in the kidney tissues from CKD patients, UUO-induced fibrotic mouse models and TGF-β1-incubated RTECs. Notably, kidney-specific knockout of Rest prominently alleviated renal fibrosis by improving mitochondrial energy metabolism and restoring fatty acid oxidation. Mechanically, REST disturbed mitochondrial energy metabolism through repressing the transcription of oxoglutarate dehydrogenase-like (OGDHL) via directly binding to its promotor region. Further, pharmacological inhibition of REST using the specific REST inhibitor, X5050, significantly ameliorated the progression of renal fibrosis both in vitro and in vivo.

Our explorations revealed the upregulation of REST in renal fibrosis disrupts mitochondrial energy metabolism through transcriptionally suppressing OGDHL, which may act as a promising therapeutic target for renal fibrosis.

Chronic kidney disease (CKD) affects over 10% of the global population and is a leading cause of mortality. Kidney fibrosis, a key endpoint of CKD, disrupts nephron tubule anatomy and filtration function, and disease pathomechanisms are not fully understood. Kidney fibrosis is currently investigated with in vivo models, that gradually support the identification of possible mechanisms of fibrosis, but with limited translational research, as they do not fully recapitulate human kidney physiology, metabolism, and molecular pathways. In vitro 2D cell culture models are currently used, as a starting point in disease modeling and pharmacology, however, they lack the 3D kidney architecture complexity and functions. The failure of several therapies and drugs in clinical trials highlights the urgent need for advanced 3D in vitro models. This review discusses the urinary system's anatomy, associated diseases, and diagnostic methods, including biomarker analysis and tissue biopsy. It evaluates 2D and in vivo models, highlighting their limitations. The review explores the state-of-the-art 3D-humanized in vitro models, such as 3D cell aggregates, on-chip models, biofabrication techniques, and hybrid models, which aim to mimic kidney morphogenesis and functions. These advanced models hold promise for translating new therapies and drugs for kidney fibrosis into clinics.