Renal Fibrosis Research Articles

Spironolactone protects against hypertension-induced renal fibrosis by promoting autophagy and inhibiting the NLRP3 inflammasome.

We aimed to investigate the mechanism by which spironolactone protects against hypertensive renal fibrosis. For in-vivo experiments, we established Control, SHR, and SHR+spironolactone (20 mg/kg/day) groups. For in-vitro experiments, we established Control, TGF-β1-induced (10 ng/ml), and spironolactone (1 μmol/l) intervention groups. Renal function and serum potassium, estradiol, testosterone, and plasma aldosterone levels were assessed, along with autophagy indicators LC3 and p62, and NLRP3 inflammasome-related proteins (NLRP3, caspase-1, IL-1β and IL-18). Additionally, changes in macrophage polarization and T cell and dendritic cell populations were determined. 20 mg/kg/day of spironolactone effectively maintained systolic pressure and renal function by lowering aldosterone levels and significantly reducing testosterone levels. Hypertensive renal fibrosis was predominant in the glomeruli, tubules, and interstitium, and was associated with autophagy inhibition in renal tubules, NLRP3 inflammasome activation, both M1 and M2 macrophage polarization, with a predominant effect on M1 polarization, decreased CD4+ T cell population and CD4/CD8 ratio, and increased CD8+ T cell and dendritic cell population. Autophagy negatively regulated the NLRP3 inflammasome. Spironolactone inhibited both M1 and M2 macrophages polarization, mainly M1 macrophage polarization, reduced CD8+ T and dendritic cell population, increased CD4+ T cell population, negatively regulated the release of NLRP3 inflammasome-related proteins in macrophages, and restored autophagy in the glomeruli and renal tubules. Spironolactone acts on sites where the mineralocorticoid receptor is present. A dose of 20 mg/kg/day spironolactone is well tolerated and protects against hypertension-induced renal fibrosis by restoring autophagy and suppressing NLRP3 inflammasome activation.

Renometabolic disorder in experimental rat model of polycystic ovarian syndrome is reversed by acetate-mediated inhibition of pyruvate dehydrogenase kinase 4

BackgroundChronic Kidney disorders is a global public health problem, including in women with polycystic ovarian syndrome (PCOS), and is characterized by renal fibrosis, nephrotoxicity and glomerulonephritis, which increases the possibility of renal failure and organ transplant. Pyruvate dehydrogenase kinase 4 (PDK4) has been implicated in mitochondria dysfunction, contributing to metabolic dysregulation in different organs, including kidney. Studies have shown that short chain fatty acids, particularly acetate, alleviates metabolic alterations in experimental models. Hence, the present study investigated the therapeutic potential of acetate on renometabolic disorders associated with experimental PCOS model. The study in addition elucidates the probable involvement of PDK4 in PCOS-associated renometabolic disorders.MethodsEight-week-old nulliparous female Wistar rats were randomly allotted into four groups (n = 5). Letrozole (1 mg/kg bw) was used to induce PCOS for 3 weeks. Thereafter, acetate (200 mg/kg bw) was administered for 6 weeks, uninterruptedly. Biochemical parameters from the plasma and renal tissue, as well as histology of ovaries were performed with appropriate methods.ResultsExperimental PCOS rats were characterized with elevated circulating testosterone and the presence of multiple ovarian cysts. In addition, rat with PCOS also manifested insulin resistance, increased plasma urea and creatinine levels, increased renal Gamma glutamyl transferase (GGT), malondialdehyde (MDA), Nuclear factor -kappa B (NF-kB), Tumor necrosis factor -alpha (TNF-a), Transforming growth factor -beta 1 (TGF-B1), caspase-6, Histone deacetylase 2 (HDAC2), while a decrease in glucose-6 phosphate dehydrogenase (G6PD), reduced glutathione (GSH), renal nitric oxide (NO) and endothelial nitric oxide synthesis (eNOS), when compared with animals in the control group. These were associated with elevated level of PDK4 in the renal tissue. However, administration of acetate ameliorates these renal/metabolic abnormalities.ConclusionAltogether, the results from the present study suggests that acetate ameliorates renal dysfunction in PCOS via downregulation of PDK4.

Stromal vascular fraction inhibits renal fibrosis by regulating metabolism and inflammation in obstructive nephropathy

Stromal vascular fraction inhibits renal fibrosis by regulating metabolism and inflammation in obstructive nephropathy

EphrinB2 Ameliorates Renal Fibrosis by Inhibiting the TGF-β/Smad3 Signaling Pathway and the Inflammation Response.

EphrinB2 is known to play a variety of roles in the pathological process of fibrosis in the heart, skin, and retina, according to current research. However, the role of Ephrin- B2 in renal fibrosis remains to be clarified. We aimed to investigate the role of EphrinB2 in the renal fibrosis model and its underlying mechanisms. Unilateral ureteral obstruction (UUO) models and TGF-β-treated renal tubular epithelial cells (HK2) were adopted in this study to determine if EphrinB2 could lead to renal fibrosis. EphrinB2 was highly expressed in renal tubular cells in UUO mice. Using adeno-associated virus (AAV)-mediated EphrinB2 overexpression, we observed significant improvements in renal function and injury, as well as a marked reduction in fibrosis. For example, EphrinB2 overexpression decreased the expression of fibrosis markers such as Fibronectin and α-SMA by approximately 40%. In vitro, EphrinB2 also significantly reduced extracellular matrix (ECM) deposition and cellular fibrosis under TGF-β stimulation. Mechanistically, EphrinB2 inhibited TGF-β/Smad3 signaling by approximately 40%, and reduced inflammatory markers such as MCP1 and IL-1β by approximately 60% and 35%, respectively. This study uncovered a previously unrecognized anti-fibrotic role of EphrinB2 in renal fibrosis, which is achieved through the prevention TGF-β/Smad3 signaling and inflammation response. It seemed that EphrinB2 might be a promising therapeutic target in the treatment of fibrotic diseases and kidney failure.

Nephropathy II Decoction Attenuates Renal Fibrosis via Regulating TLR4 and Gut Microbiota Along the Gut-Kidney Axis.

Nephropathy II Decoction (NED) is a widely used Chinese medicinal formulation for managing chronic kidney disease (CKD). Despite its extensive application, the precise mechanisms underlying its therapeutic effects remain poorly understood. This study aims to elucidate the role of NED in attenuating renal fibrosis and to explore its impact on the gut-kidney axis. The principal constituents of NED were analyzed using ultra-performance LC-tandem mass spectrometry (UPLC-MS/MS). A bilateral renal ischemia-reperfusion injury (bIRI) model was employed to induce fibrosis. RT-qPCR was utilized to assess the expression of mRNA related to the toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) and nuclear factor-κB (NF-κB) signaling pathway. Western blotting analysis was performed to identify changes in renal fibrosis markers, TLR4/MyD88/NF-κB pathway proteins, and the colon proteins ZO-1 and Occludin-1. Serum levels of uremic toxins were quantified using enzyme-linked immunosorbent assay (ELISA), and 16S ribosomal RNA (rRNA) gene sequencing was conducted to explore changes in the gut microbiome of the mice. Our study demonstrated that mice in the NED group exhibited reduced serum creatinine, blood urea nitrogen, and urinary protein levels, alongside improvements in kidney damage and a decrease in renal fibrosis markers. In the bIRI group, TLR4/MyD88/NF-κB protein and mRNA levels, as well as intestinal tight junction proteins and enterogenic uremic toxins, were significantly reduced. NED treatment reversed these changes and modified the gut microbiota. Furthermore, fecal microbial transplantation (FMT) alleviated kidney damage and fibrosis in bIRI mice. In summary, NED ameliorates kidney injury and fibrosis by modulating the gut microbiota and may further attenuate fibrosis through the inhibition of TLR4 expression, thereby influencing the gut-kidney axis.

The role of ERK1/2 signaling in diabetes: pathogenic and therapeutic implications

ERK1/2 (extracellular signal-regulated kinase 1/2) is an important member of the MAPK (mitogen-activated protein kinase) family and is widely involved in many biological processes such as cell proliferation, differentiation, apoptosis and migration. After activation by phosphorylation, ERK1/2 can be transferred into the nucleus and directly or indirectly affect the activity of transcription factors, thereby regulating gene expression. More and more studies have shown that ERK1/2 plays an important role in diabetes and its complications, such as insulin secretion, islet β cell function, diabetic cardiomyopathy, diabetic nephropathy, renal fibrosis, lipogenesis, diabetic vasculopathy, etc. These effects reveal the complexity and diversity of the ERK1/2 signaling pathway in the pathogenesis of diabetes, and its activation and inhibition mechanisms in multiple physiological and pathological processes provide potential targets for diabetes treatment. The purpose of this mini-review is to explore the key role of ERK1/2 in diabetes and the progress of research on targeted inhibitors of ERK1/2, which provides new strategies for the treatment of diabetes.

Renal tubular epithelial IGFBP7 interacts with PKM2 to drive renal lipid accumulation and fibrosis.

Renal tubular epithelial IGFBP7 interacts with PKM2 to drive renal lipid accumulation and fibrosis.

Hypertension in living kidney donors has no effect on complement activation and fibrosis.

In the past, elevated blood pressure was considered an exclusion criterion for living kidney donation because of concerns about premature kidney failure. Hypertension leads to complement deposits and renal fibrosis in the kidney. Therefore, the aim of this study was to investigate whether increased complement deposits and fibrosis can be observed in grafts of hypertensive compared to normotensive living donors. Zero-time renal biopsies from 238 living donors (52 hypertensive) and the corresponding one-year protocol biopsies were examined for complement deposits of C1q, C3c, and MASP-2. Findings were compared to kidney biopsies from patients with hypertensive nephropathy. Further, renal fibrosis was visualized by Sirius Red staining, scored semiquantitatively and compared to biopsies from deceased donors and kidneys with hypertensive nephropathy. Additionally, zero-time biopsies from hypertensive (n = 6) and normotensive (n = 5) living donors were analyzed for expression of fibrosis-associated genes by multiplex mRNA analysis and compared to zero-time biopsies (n = 6) from deceased donors. In all zero-time biopsies from living donors, complement deposits were minimal for C1q, C3c, and MASP-2 compared to samples with hypertensive nephropathy, regardless of whether the donor was hypertensive or normotensive. In one-year protocol biopsies, complement deposits were unchanged, while renal fibrosis was slightly but not significantly increased in hypertensive compared to normotensive living donors. Gene expression data showed that the 11 zero-time biopsies from hypertensive and normotensive living donors clustered together, and were clearly separated from the deceased donor biopsies. The use of kidneys from hypertensive living donors appears to have no or little effect on renal complement deposits and fibrosis one year after transplantation.

Compound probiotics alleviate hyperuricemia-induced renal injury via restoring gut microbiota and metabolism

To investigate the role and mechanisms of gut microbiota in hyperuricemia-induced renal injury, we established renal failure models using unilateral nephrectomized mice. After four weeks of adenine and potassium oxalate-supplemented diet, probiotic intervention was administered. Renal pathological and functional changes were assessed through H&E staining and plasma biochemical analysis. Gut microbiota composition and metabolite profiles were evaluated using 16 S rRNA gene sequencing and non-targeted metabolomics of fecal samples.Our findings demonstrate that the compound probioticS effectively attenuated hyperuricemia-associated renal dysfunction and interstitial fibrosis. The intervention reduced oxidative stress, mitophagy, and apoptosis in renal tubules. Probiotic treatment enhanced gut microbiota diversity, notably increasing the abundance of Prevotella_9, Dorea, and unclassified Bacteroidota, while decreasing unclassified Desulfovibrio. KEGG enrichment analysis revealed that probiotic intervention upregulated arginine and proline metabolism, as well as tyrosine metabolism in feces. Furthermore, it enhanced the metabolism of arginine, proline, valine, leucine, and isoleucine in plasma.Notably, sulfocholic acid and urocanic acid showed negative correlations with oxidative stress markers, autophagy, and apoptosis indicators. Similarly, plasma L-proline levels were inversely correlated with these pathological parameters.These results suggest that the compound probiotics may mitigate hyperuricemia-induced kidney damage through restoration of gut microbiota homeostasis and preservation of plasma and fecal metabolites. The protective mechanisms likely involve attenuation of hyperuricemia-associated oxidative stress, mitochondrial dysregulation, and phagocytosis-induced apoptosis.Our study provides compelling evidence that probiotic supplementation represents a promising therapeutic strategy for hyperuricemia-induced renal injury, potentially through modulation of gut microbiota and associated metabolic pathways.

The Therapeutic Potential of METTL3 Inhibition in Modulating N6-Methyladenosine for Chronic Kidney Disease

Chronic kidney disease (CKD) is a progressive disease with limited therapeutic options, necessitating novel approaches for disease management. N6-methyladenosine (m6A) modification has emerged as a key regulator of gene expression in CKD, influencing pathways involved in inflammation, fibrosis, and cellular stress. METTL3 plays a crucial role in modifying RNA, with its overexpression linked to the activation of pro-fibrotic and inflammatory signaling pathways, such as TGF-1 and NF-B. Consequently, METTL3 inhibition has been explored as a potential therapeutic strategy for CKD. Preclinical studies suggest that METTL3 inhibitors can attenuate renal fibrosis, reduce inflammation, and restore oxidative stress and apoptosis by modulating m6A-dependent gene expression. However, challenges remain in developing selective and bioavailable METTL3 inhibitors, understanding the context-dependent effects of m6A modifications, and ensuring precise targeting in renal cells. Advances in small-molecule drug discovery, RNA-based therapies, and nanoparticle-mediated delivery may improve the clinical applicability of METTL3 inhibitors. Future research should focus on optimizing these therapeutic strategies to enhance efficacy while minimizing off-target effects. By targeting aberrant m6A methylation, METTL3 inhibition represents a promising avenue for CKD treatment, offering new possibilities for precision medical science.

Protective effects and mechanisms of cynaroside on renal fibrosis in mice with unilateral ureteral obstruction

ABSTRACT Renal fibrosis is a key factor in the progression of chronic kidney disease (CKD), and current treatments remain inadequate. In this study, we investigated the therapeutic effects of cynaroside (Cyn), a natural flavonoid, in a mouse model of renal fibrosis induced by unilateral ureteral obstruction. Cyn treatment significantly ameliorated tubular injury and interstitial fibrosis while improving renal function. Mechanistically, Cyn inhibited the expression of fibrosis-related proteins and suppressed Smad2/3 phosphorylation. Additionally, Cyn reduced myofibroblast accumulation by inhibiting epithelial–mesenchymal transition, as indicated by increased E-cadherin expression and decreased levels of mesenchymal markers. Cyn also reduced oxidative stress by downregulating the prooxidant enzyme NADPH oxidase 4 and restoring antioxidant enzymes. Furthermore, Cyn attenuated ferroptosis by regulating key proteins, including acyl-CoA synthetase long-chain family member 4, transferrin receptor 1, and glutathione peroxidase 4, while also restoring glutathione levels. Cyn alleviated endoplasmic reticulum stress, as evidenced by the downregulation of key markers such as glucose-regulated protein 78 and activating transcription factor 6, and reduced inflammation, as confirmed by decreased macrophage infiltration and lower cytokine production. Overall, Cyn demonstrated broad protective effects against renal fibrosis by modulating oxidative stress, ferroptosis, ER stress, and inflammation, positioning it as a potential therapeutic agent for CKD management.

Diagnostic accuracy of shear wave elastography in evaluating renal fibrosis in children with chronic kidney disease: a comparative study with Tc-99 DMSA renal scan

BackgroundChronic kidney disease (CKD) is a global public health issue, impacting over 10% of the world’s population, amounting to more than 800 million individuals. However, the true number of people affected by CKD could be much higher due to increasing risk factors like obesity, hypertension, and diabetes. CKD is a progressive condition leading to tubular atrophy and interstitial fibrosis, encompasses a variety of diseases that impair the structure and function of the kidneys.AimTo evaluate the accuracy of shear wave elastography to detect renal parenchymal fibrosis in children with chronic kidney disease in comparison with technetium-99 m dimercaptosuccinic acid (DMSA) scan.MethodsA case–control study. Cases were pediatric patients with CKD who referred for DMSA scan from the pediatric hospital while the controls are recruited from the pediatric outpatient clinics referred for an abdominal ultrasound for reasons other than renal pathology at the radiology department of our institution. Both cases and control group underwent ultrasound examination with shear wave elastography.ResultsThe average elasticity values from 20 controls taken in our study were 11.02(9.58–11.5) kpa. In our study shear wave elastography (SWE) could predict scar on DMSA at a cutoff elasticity value of ≥ 12.065 kpa with a sensitivity of 85.71 and specificity of 92.31. No significant difference in SWE values between controls and cases without scaring.ConclusionsSWE is an affordable, widely available, and noninvasive technique with no radiation risk, making it valuable for monitoring disease progression and follow-up in children with CKD. Its high sensitivity and specificity in detecting renal scarring further enhance its clinical utility.

Therapeutic potential of voltage-dependent potassium channel subtype 1.3 blockade in alleviating macrophage-related renal inflammation and fibrogenesis

Macrophage polarization and infiltration are notable characteristics of kidney injury and fibrosis. Although voltage-dependent potassium channel subtype (Kv) 1.3 is involved in macrophage-induced inflammation, its precise mechanism has not been elucidated. Therefore, this study aimed to explore the role of Kv1.3 in renal injury and macrophage polarization. Herein, mouse models of kidney injury were established through unilateral ureteral obstruction (UUO) and ischemia-reperfusion injury (IRI). For intervention, a selective Kv1.3 blocker, margatoxin (MgTx), was administered intraperitoneally. Blood and kidney samples were collected on days 3 and 7 following UUO surgery to evaluate renal Kv1.3 expression, kidney injury, macrophage polarization changes, cytokine levels, phosphorylation of extracellular signal-regulated kinase (ERK) and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB). Kidney samples were also collected 24 h after IRI to assess kidney injury and evaluate renal Kv1.3 expression, as well as the phosphorylation levels of ERK and NF-κB. Histological analysis of MgTx-treated UUO and IRI mice revealed that Kv1.3 inhibition markedly alleviated renal damage induced by UUO and IRI, substantially reducing the levels of myofibroblast markers, specifically α-smooth muscle actin and transforming growth factor-β1. In UUO mice, Kv1.3 expression and proportions of monocyte-derived cells in peripheral blood and M1 macrophages notably increased but reversed after MgTx treatment, indicating diminished macrophage infiltration. Additionally, MgTx treatment downregulated various M1-related proinflammatory markers, including tumor necrosis factor-α, inducible nitric oxide synthase, and interleukin (IL)-1β, and upregulated M2-associated markers such as IL-10, arginase-1, and CD206. Moreover, Kv1.3 overexpression in THP-1 cells upregulated M1 macrophage markers and proinflammatory cytokines, enhanced their migratory ability. This indicates an increased polarization towards the M1 phenotype, which correlates with impaired renal tubular epithelial cells. Notably, Kv1.3 upregulation both in vivo and in vitro led to increased phosphorylation of ERK and NF-κB, possibly promoting M1 macrophage polarization. This study establishes Kv1.3 as a pivotal regulator of renal fibrosis and macrophage polarization, showing that its inhibition leads to reduced infiltration and migration of M1 macrophages, mitigation of renal injury via suppression of ERK/NF-κB signaling. Altogether, these findings suggest the potential of Kv1.3 as a promising therapeutic target for renal fibrosis.

Calpain1 inhibition enhances autophagy-lysosomal pathway and ameliorates tubulointerstitial fibrosis in Nephronophthisis

BackgroundNephronophthisis (NPH) is classified under the category of renal ciliopathies and is the most common genetic disease leading to renal failure in children. Early-onset and progressive renal tubulointerstitial fibrosis represents one of the most significant features, culminating in renal insufficiency. However, the molecular mechanism of tubulointerstitial fibrosis remains unclear. Previously, we constructed an NPH mouse model via CRISPR-Cas9. This mouse model demonstrated typical features of tubulointerstitial fibrosis. In this study, we aimed to explore the pathogenesis of tubulointerstitial fibrosis in NPH and identify early intervention targets in both the NPH models and patients.MethodsIn this study, transcriptome changes in mouse kidneys were analyzed through RNA sequencing to explore the molecular mechanisms of renal tubulointerstitial fibrosis in NPH. We found an increased abundance of calpain1 in both the NPH models and patients. Pathway enrichment analysis indicated autophagy-lysosomal pathway was altered in the NPH models. Western blot, immunofluorescence or immunohistochemical staining were used to verify the expression of calpain1. We also detected autophagy activities in NPH models by lysotracker staining and transmission electron microscopy (TEM). Epithelial or mesenchymal-specific markers and Masson’s trichrome staining were used to detect the status of tubulointerstitial fibrosis. Furthermore, NPH models were treated with a calpain1 inhibitor to explore the role of calpain1 in autophagy-lysosomal pathway and tubulointerstitial fibrosis.ResultsThe increased abundance of calpain1 impaired the autophagy-lysosomal pathway and induced tubulointerstitial fibrosis by promoting epithelial-to-mesenchymal transition. On the other hand, calpain1 inhibition could enhance the autophagy-lysosomal pathway and ameliorate the phenotypes of tubulointerstitial fibrosis in NPH models.ConclusionsCalpain1-mediated autophagy-lysosomal pathway disorder may be an important cause of tubulointerstitial fibrosis in NPH. Calpain1 may have therapeutic implications for renal tubulointerstitial fibrosis.

Raspberry ameliorates renal fibrosis in rats with chronic kidney disease via the PI3K/Akt pathway.

Raspberry ameliorates renal fibrosis in rats with chronic kidney disease via the PI3K/Akt pathway.

Role of peroxisomes in the pathogenesis and therapy of renal fibrosis.

Role of peroxisomes in the pathogenesis and therapy of renal fibrosis.

Ginsenoside Rg1 attenuates T2DM-induced renal damage and fibrosis by inhibiting TRPC6-ChREBP-TXNIP signaling.

Ginsenoside Rg1 attenuates T2DM-induced renal damage and fibrosis by inhibiting TRPC6-ChREBP-TXNIP signaling.

Fructus arctii mitigates diabetic nephropathy via the Apoh/PPAR-γ pathway.

Fructus arctii mitigates diabetic nephropathy via the Apoh/PPAR-γ pathway.

Root of Prunus persica (taoshugen) ameliorated renal fibrosis by inhibiting TGF-β signaling via upregulating Pmepa1 in mice with unilateral ureter obstruction.

Root of Prunus persica (taoshugen) ameliorated renal fibrosis by inhibiting TGF-β signaling via upregulating Pmepa1 in mice with unilateral ureter obstruction.

Discovered cassane diterpenoids from Caesalpinia mimosoides lam. Exhibited anti-renal fibrosis activity via regulating TGF-β1/Smads signaling pathway.

Discovered cassane diterpenoids from Caesalpinia mimosoides lam. Exhibited anti-renal fibrosis activity via regulating TGF-β1/Smads signaling pathway.