Search Results (364)

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and devastating lung disorder. In response to transforming growth factor-β (TGF-β), normal lung cells proliferate and differentiate into myofibroblasts, which are instrumental in promoting disease progression. Small interfering RNA (siRNA) targeting heat shock protein 47 (HSP47) has been demonstrated to alleviate IPF by blocking collagen synthesis and secretion. Exosomes (EXOs) have been investigated for drug delivery due to their superior carrier properties. However, their loading efficiency has been a limiting factor in widely application as drug carriers. In this study, an ultrasonic microfluidic method was employed to enhance the loading efficiency of siHSP47 into EXOs, achieving 31.1% efficiency rate. EXOs were isolated from human embryonic kidney cells (293F) and loaded with siHSP47 (EXO-siHSP47). The findings indicated that EXO-siHSP47 penetrated the collagen barrier and effectively silenced HSP47 expression in activated fibroblasts in vitro. Western blotting and immunofluorescence analyses confirmed that EXO-siHSP47 significantly reduced the secretion and deposition of extracellular matrix (ECM) proteins. Wound healing and Transwell migration assays demonstrated that EXO-siHSP47 inhibited fibroblast differentiation and migration. In conclusion, 293F-derived EXOs loaded with siHSP47 present a promising therapeutic strategy for IPF. Full article

Background: Recent findings have highlighted that abnormal energy metabolism is a key feature of autosomal-dominant polycystic kidney disease (ADPKD). Emerging evidence suggests that nutritional ketosis could offer therapeutic benefits, including potentially slowing or even reversing disease progression. This systematic review aims to synthesise the literature on ketogenic interventions to evaluate the impact in ADPKD. Methods: A systematic search was conducted in Medline, Embase, and Scopus using relevant Medical Subject Headings (MeSH) and keywords. Studies assessing ketogenic interventions in the management of ADPKD in both human and animal models were selected for data extraction and analysis. Results: Three animal reports and six human studies were identified. Ketogenic diets (KD) significantly slowed polycystic kidney disease (PKD) progression in rats with improved renal function and reduced cystic areas. There was reduced renal fibrosis and cell proliferation. The supplementation of beta-hydroxybutyrate (BHB) in rats also reduced PKD progression in a dose-dependent manner. Human studies (n = 129) on KD in ADPKD reported consistent body mass index (BMI) reduction across trials, with an average weight loss of ∼4 kg. Improvements in blood pressure were also noted. Ketosis was achieved in varying degrees. Effects on kidney function (eGFR) were beneficial. Results for kidney volume were mixed but most studies were underpowered for this outcome. Lipid profiles showed increases in total cholesterol (∼1 mmol/L) and LDL cholesterol (∼0.4 mmol/L) in most studies. Safety concerns such as “keto flu” symptoms, elevated uric acid levels, and occasional kidney stones were noted. Overall feasibility and adherence to the KD were rated positively by most participants. Conclusions: Human studies are promising; however, they have been limited by small sample sizes and short durations. Larger, long-term trials are needed to assess the efficacy, adherence, and safety of ketogenic diets in people with ADPKD. Full article

Chronic kidney disease (CKD) is a major public health concern around the world. It is a significant risk factor for cardiovascular disease (CVD), and, as it progresses, the risk of cardiovascular events increases. Furthermore, end-stage kidney disease severely affects life expectancy and quality of life. Type 2 diabetes and hypertension are not only primary causes of CKD but also independent risk factors for CVD, which underscores the importance of effective treatment strategies for these conditions. The current therapies, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and sodium–glucose co-transporter 2 inhibitors, are administered to control hypertension, slow the progression of CKD, and reduce cardiovascular risk. However, their efficacy remains suboptimal in certain instances. Mineralocorticoid receptor (MR), a nuclear receptor found in various tissues, such as the kidney and heart, plays a pivotal role in the progression of CKD. Overactivation of MR triggers inflammation and fibrosis, which exacerbates kidney damage and accelerates disease progression. MR antagonists (MRAs) have substantial beneficial effects in patients with cardiac and renal conditions; however, their use has been constrained because of adverse effects, such as hyperkalemia and kidney dysfunction. Recently, novel non-steroidal MRAs are more efficacious and have superior safety profiles to steroidal MRAs, making them promising potential components of future treatment strategies. Here, we discuss recent findings and the roles of MRAs in the management of hypertension and CKD, with a focus on the evidence obtained from fundamental research and major clinical trials. Full article

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. Full article

Chronic kidney disease (CKD) progresses through mechanisms involving inflammation, fibrosis, and oxidative stress, leading to the gradual structural and functional deterioration of the kidneys. Tormentic acid (TA), a triterpenoid compound with known anti-inflammatory and antioxidant properties, shows significant potential in counteracting these pathological processes. This study explored the protective role of TA in a unilateral ureteral obstruction (UUO)-induced CKD model. Mice received TA through intraperitoneal injections at a dosage of 5 mg/kg per day for 8 consecutive days, commencing a day before the UUO procedure. The TA treatment significantly improved both structural and functional kidney injury. It suppressed cytokine expression and reduced immune cell infiltration, inhibited the activation of the mitogen-activated protein kinase cascade, and alleviated endoplasmic reticulum stress. Moreover, TA displayed potent anti-fibrotic effects by reversing epithelial-to-mesenchymal transition and inhibiting Smad2/3 activation, reducing extracellular matrix deposition. TA also mitigated oxidative stress by attenuating lipid peroxidation and boosting antioxidant defenses. Additionally, it inhibited apoptosis and ferroptosis by reducing oxidative stress and modulating key cell death markers. Collectively, these findings indicate that TA provides comprehensive renoprotection in the UUO model by effectively targeting inflammation, fibrosis, oxidative stress, and tubular cell death in CKD progression. Full article

Background/Objectives: Interstitial fibrosis/tubular atrophy in kidney transplantation is an unspecific lesion induced by immune and non-immune factors, which determines the progression of chronic kidney disease. Hydroxyproline is an imino acid that is part of the molecule of collagen. The aim of this study was to assess hydroxyproline in urine microvesicles as a marker of fibrosis in the renal transplant patient. Patients and Methods: An observational cross-sectional study was conducted on 46 renal transplant patients who had undergone renal biopsy with diagnostic intention, as well as 19 healthy controls. Clinical, histological, and laboratory variables were collected at the time of marker determination and renal function was analyzed 2 years later. Hydroxyproline was measured in urine microvesicles. Results: Renal transplant patients showed a higher microvesicular concentration of hydroxyproline compared to the control group, with the following medians (interquartile range (IQR)): 28.024 (5.53) ng/mL vs. 2.51 (1.16) ng/mL, p < 0.001. In the transplanted patients, patients in whom biopsy showed some score of total cortical parenchymal inflammation (ti) displayed a significantly higher concentration of hydroxyproline in urine microvesicles than those patients who did not score for cortical parenchymal inflammation (29.91 ± 2.797 ng/mL vs. 22.72 ± 8.697 ng/mL, p = 0.034). No significant correlation was observed between urinary markers and serum creatinine, calcium, and parathyroid hormone (PTH). Conclusions: The concentration of hydroxyproline in urinary microvesicles increased in renal transplant patients relative to healthy controls. Hydroxyproline in urinary microvesicles is a marker of chronic renal inflammation in transplanted patients, and further studies are required to confirm this finding in other pathologies, as well as the association with fibrosis and the evolution of renal function. Full article

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease. Current treatments for DKD do not halt renal injury progression, highlighting an urgent need for therapies targeting key disease mechanisms. Our previous studies demonstrated that activating the Sigma-1 receptor (S1R) with fluvoxamine (FLU) protects against acute kidney injury by inhibiting inflammation and ameliorating the effect of hypoxia. Based on these, we hypothesized that FLU might exert a similar protective effect in DKD. Diabetes was induced in male Wistar rats using streptozotocin, followed by a seven-week FLU treatment. Metabolic and renal parameters were assessed along with a histological analysis of glomerular damage and fibrosis. The effects of FLU on inflammation, hypoxia, and fibrosis were tested in human proximal tubular cells and normal rat kidney fibroblasts. FLU improved renal function and reduced glomerular damage and tubulointerstitial fibrosis. It also mitigated inflammation by reducing TLR4, IL6, and NFKB1 expressions and moderated the cellular response to tubular hypoxia. Additionally, FLU suppressed TGF-β1-induced fibrotic processes and fibroblast transformation. These findings suggest that S1R activation can slow DKD progression and protect renal function by modulating critical inflammatory, hypoxic, and fibrotic pathways; therefore, it might serve as a promising novel drug target for preventing DKD. Full article

Hypertension exerts a profound impact on the microcirculation, causing both structural and functional alterations that contribute to systemic and organ-specific vascular damage. The microcirculation, comprising arterioles, capillaries, and venules with diameters smaller than 20 μm, plays a fundamental role in oxygen delivery, nutrient exchange, and maintaining tissue homeostasis. In the context of hypertension, microvascular remodeling and rarefaction result in reduced vessel density and elasticity, increasing vascular resistance and driving end-organ damage. The pathophysiological mechanisms underlying hypertensive microvascular dysfunction include endothelial dysfunction, oxidative stress, and excessive collagen deposition. These changes impair nitric oxide (NO) bioavailability, increase reactive oxygen species (ROS) production, and promote inflammation and fibrosis. These processes lead to progressive vascular stiffening and dysfunction, with significant implications for multiple organs, including the heart, kidneys, brain, and retina. This review underscores the pivotal role of microvascular dysfunction in hypertension-related complications and highlights the importance of early detection and therapeutic interventions. Strategies aimed at optimizing blood pressure control, improving endothelial function, and targeting oxidative stress and vascular remodeling are critical to mitigating the systemic consequences of hypertensive microvascular damage and reducing the burden of related cardiovascular and renal diseases. Full article

Renal fibrosis is a common final pathway underlying nearly almost all progressive kidney diseases. Metal ions are essential trace elements in organisms and are involved in important physiological activities. However, aberrations in intracellular metal ion metabolism may disrupt homeostasis, causing cell death and increasing susceptibility to various diseases. Accumulating evidence suggests a complex association between metal-dependent cell death and renal fibrosis. In this article, we provide a comprehensive overview of the specific molecular mechanisms of metal-dependent cell death and their crosstalk, up-to-date evidence supporting their role in renal fibrosis, therapeutic targeting strategies, and research needs, aiming to offer a rationale for future clinical treatment of renal fibrosis. Full article

Background/Objectives: Chronic kidney disease (CKD) is a progressive pathological condition which results in the severe fibrosis of the kidneys. However, the mechanisms of CKD progression and fibrogenesis remain unclear. We wanted to examine the effects that apocynin and hyperbaric oxygen therapy (HBOT) have on renal function and structure in animals with CKD induced through 5/6 nephrectomy (5/6 Nx-L). Methods: Male Wistar rats were divided in 5 groups (n = 8/group) as follows: control—sham-operated rats; Nx-L—rats with 5/6 Nx-L; APO—5/6 Nx-L + apocynin treatment; HBOT—5/6 Nx-L + hyperbaric oxygen treatment, and APO+HBOT—5/6 Nx-L, treated with both treatments. All treatments started 4 weeks after the final step of CKD induction and lasted for 4 weeks. At the end of the experiment, urine samples were collected for the proteinuria assessment and the mean arterial pressure (MAP) was measured. Kidneys were collected for histopathological, Western blot, and immunohistochemical analyses. Results: All treatments significantly decreased MAP compared to the Nx-L group (p < 0.001). In the APO and APO+HBOT groups, the level of proteinuria was decreased compared to the Nx-L group (p < 0.05 and p < 0.01, respectively). All examined treatments significantly decreased the intensity of lesions in the kidney compared to those observed in the Nx-L group (p < 0.001). Isolated treatments with apocynin and HBOT induced a significant decrease in desmin expression compared to the Nx-L group (p < 0.05); meanwhile, they did not affect the levels of fibronectin (FN) and hypoxia-inducible factor-1α (HIF-1α). Combined treatment did not affect desmin expression levels; however, it induced a significant increase in fibronectin expression compared to Nx-L (p < 0.001). Conclusions: Apocynin treatment decreased BP and protein loss, and it improved renal morphology at least partly through the downregulation of desmin expression without changing FN and HIF-1α. Hyperbaric oxygen therapy improved hypertension but failed to significantly affect the level of proteinuria. Combined treatment (apocynin and HBOT) normalized blood pressure (BP) values, renal function, and improved kidney structure by modulating FN and HIF-1α, without affecting desmin protein expression. Further studies are needed to elucidate the mechanisms of slowing down the progression of CKD in this experimental model. Full article

Kidney fibrosis is the common pathological pathway in progressive chronic kidney disease (CKD), and current treatments are largely ineffective. The C-X-C chemokine receptor 4 (CXCR4) is crucial to fibrosis development. By using neural cell adhesion molecules as scaffolds with binding loops that mimic the shape of shark antibodies, fully humanized single-domain i-bodies have been developed. The first-generation i-body, AD-114, demonstrated antifibrotic effects in a mouse model of folic acid (FA)-induced renal fibrosis. The second-generation i-body, AD-214, is an Fc-fusion protein with an extended half-life, enhanced activity, and a mutated Fc domain to prevent immune activation. To investigate the renoprotective mechanisms of AD-214, RPTEC/TERT1 cells (a human proximal tubular cell line) were incubated with TGF-b1 with/without AD-214 and the supernatant was collected to measure collagen levels by Western blot. Mice with unilateral ureteral obstruction (UUO) received AD-214 intraperitoneally (i.p.) every two days for 14 days. Kidney fibrosis markers and kidney function were then analyzed. AD-214 suppressed TGF-b1-induced collagen overexpression in RPTEC/TERT1 cells. In UUO mice, AD-214 reduced extracellular matrix (ECM) deposition, restored kidney function, and limited leukocyte infiltration. In a scratch assay, AD-214 also inhibited macrophage migration. To conclude, i-body AD-214 attenuates UUO-induced kidney fibrosis by inhibiting leukocyte infiltration and macrophage migration. Full article

Chronic kidney disease (CKD) is a chronic disorder characterized by kidney fibrosis and extracellular matrix accumulation that can lead to end-stage kidney disease. Epithelial-to-mesenchymal transition, inflammatory cytokines, the TGF-β pathway, Wnt/β-catenin signaling, the Notch pathway, and the NF-κB pathway all play crucial roles in the progression of fibrosis. Current medications, such as renin–angiotensin–aldosterone system inhibitors, try to delay disease development but do not stop or reverse fibrosis. This review emphasizes the growing need for tailored antifibrotic medications for CKD treatment. Precision medicine, which combines proteomic, metabolomic, and genetic data, provides a practical way to personalize treatment regimens. Proteomic signatures, such as CKD273, and genetic markers, such as APOL1 and COL4A5, help in patient stratification and focused therapy development. Two recently developed antifibrotic medications, nintedanib and pirfenidone, have been proven to diminish fibrosis in preclinical animals. Additionally, research is being conducted on the efficacy of investigational drugs targeting CTGF and galectin-3 in the treatment of kidney fibrosis. Full article

IgA nephropathy (IgAN), first described in 1968, is one of the most common forms of glomerulonephritis and can progress to end-stage kidney disease (ESKD) in 25 to 30 percent of patients within 20 to 25 years from the onset. It is histologically characterized by mesangial proliferation with prominent IgA deposition. The prognosis may be difficult to predict, but important risk factors for disease progression of kidney disease have been recognized: usually proteinuria above 0.75–1 g/day with or without hematuria, hypertension, high-risk histologic features (such as crescent formation, immune deposits in the capillary loops, mesangial deposits, glomerulosclerosis, tubular atrophy, interstitial fibrosis, and vascular disease), and a reduced Glomerular Filtration Rate (GFR). In the absence of reliable specific biomarkers, current standards of care are addressed to decrease proteinuria, as a surrogate endpoint, and control blood pressure. For a long time, corticosteroids have been considered the only cure for proteinuric patients or those at risk of progression to ESKF; however, unfortunately, like other immunosuppressive agents, they are burdened with high collateral risks. Therefore, optimal treatment remains a challenge, even if, to date, clinicians have many more options available. Here, we will review the main therapies proposed, such as the stronghold of RAAS inhibition and the use of SGLT2 inhibitors; it is expected that ongoing clinical trials may find other therapies, apart from corticosteroids, that may help improve treatment, including both immunosuppressive monoclonal antibodies and other strategies. At the current time, there are no disease-specific therapies available for IgAN, because no largescale RCTs have demonstrated a reduction in mortality or in major adverse kidney or cardiovascular events with any therapy. Full article

Long regarded as illicit substances with no clinical value, N-dimethylated tryptamines—such as N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, and bufotenine—have been found to produce naturally in a wide variety of species, including humans. Known for their psychoactive effects through serotonin receptors (5-HTRs), N-dimethylated tryptamines are currently being reinvestigated clinically for their long-term benefits in mental disorders. Endogenous tryptamine is methylated by indolethylamine-N-methyltransferase (INMT), which can then serve as an agonist to pro-survival pathways, such as sigma non-opioid intracellular receptor 1 (SIGMAR1) signaling. Fibrogenic diseases, like metabolic-associated fatty liver disease (MAFLD), steatohepatitis (MASH), and chronic kidney disease (CKD) have shown changes in INMT and SIGMAR1 activity in the progression of disease pathogenesis. At the cellular level, endothelial cells and fibroblasts have been found to express INMT in various tissues; however, little is known about tryptamines in endothelial injury and fibrosis. In this review, I will give an overview of the biochemistry, molecular biology, and current evidence of INMT’s role in hepatic fibrogenesis. I will also discuss current pre-clinical and clinical findings of N-methylated tryptamines and highlight new and upcoming therapeutic strategies that may be adapted for mitigating fibrogenic diseases. Finally, I will mention recent findings for mutualistic gut bacteria influencing endogenous tryptamine signaling and metabolism. Full article

Kidney fibrosis is a hallmark of chronic kidney diseases. Evidence shows that genetic variability and complement component 3 (C3) might influence tubulointerstitial fibrosis. Still, the role of renal C3 production in the epithelial-to-mesenchymal transition (EMT) and genetically determined fibrosis progression remains undiscovered. The kidneys of fibrosis-resistant C57Bl/6J (B6) and fibrosis-prone CBA/J (CBA) and BALB/cJ (BalbC) mice (n = 4–8/group) were subjected to unilateral ureteral obstruction (UUO) and analyzed after 1, 3, and 7 days, along with human focal glomerular sclerotic (FSGS) and healthy kidneys. Mouse primary tubular epithelial cells (PTECs) were investigated after 24 h of treatment with transforming growth factor β (TGFβ) or complement anaphylatoxin 3a (C3a) agonist (n = 4/group). UUO resulted in delayed kidney injury in fibrosis-resistant B6 mice, but very early renal C3 messenger RNA (mRNA) induction in fibrosis-prone CBA and BalbC mice, along with collagen I (Col1a1) and collagen III (Col3a1). CBA depicted the fastest fibrosis progression with the highest C3, lipocalin-2 (Lcn2), Tgfb1, and chemokine (C-C motif) ligand 2 (Ccl2) expression. Human FSGS kidneys depicted C3 mRNA over-expression and strong tubular C3 immunostaining. In PTECs, C3a agonist treatment induced pro-fibrotic early growth response protein 1 (EGR1) expression and the EMT, independent of TGFβ signaling. We conclude that de novo renal tubular C3 synthesis is associated with the genetically determined kidney fibrosis progression rate in mice and the pathogenesis of FSGS in humans. This tubular C3 overproduction can, through local pro-fibrotic effects, influence the progression of chronic kidney disease. Full article