Search Results (338)

Phosphate (Pi) and calcium (Ca²⁺) are essential mineral ions that play coordinated roles in maintaining normal cellular functions. While various steps of calcium signaling are well characterized, emerging evidence suggests the critical role of both intracellular and extra cellular phosphate in regulating intracellular Ca²⁺. In the cytoplasm, phosphate influences ATP production and organelle calcium buffering and influences the activity of calcium pumps, such as sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA) and the plasma membrane Ca²⁺-ATPase (PMCA). Extracellular phosphate, taken up via sodium-dependent phosphate transporters, triggers signaling cascades that affect the processes of calcium influx, storage, and release. Additionally, high extracellular phosphate levels can disrupt calcium homeostasis through the systemic interactions of hormones such as fibroblast growth factor 23 (FGF23), vitamin D and parathyroid hormone (PTH), especially under pathological conditions such as chronic kidney disease (CKD). This article briefly summarizes the current understanding of the bidirectional influence of intra- and extracellular phosphate on calcium dynamics at the cellular level, with a focus on the underlying mechanisms. Full article

Fibroblasts and lymphangiogenesis promote renal fibrosis. However, whether fibroblasts promote renal fibrosis via lymphangiogenesis has not yet been fully elucidated. This study set out to clarify whether aldosterone induces fibroblast transdifferentiation into lymphatic endothelial-like cells, thus promoting lymphangiogenesis and renal fibrosis. In vivo, twenty-four male Wistar rats were randomized into Sham, ALD (6-week aldosterone infusion), and ALD + ESA (aldosterone infusion with esaxerenone co-treatment) groups. In vitro, primary rat renal interstitial fibroblasts (RKFs) were used. Immunohistochemistry and Western blot were used to detect lymphatic endothelial and fibroblast marker expression in kidneys from aldosterone-infused rats and RKFs. Their co-expression was determined by flow cytometry and immunofluorescence co-staining. Mineralocorticoid receptor (MR) activation and related signaling pathways were also analyzed by Western blot, immunohistochemistry, and flow cytometry. Additionally, RKF migration and tube formation were examined to investigate the role of aldosterone-induced fibroblast-to-lymphatic endothelial-like transdifferentiation in renal fibrosis. Our data suggest that aldosterone activates the MR and induces the transdifferentiation of fibroblasts into lymphatic endothelial-like cells via the MR/VEGFC/VEGFR-3 pathway, thereby promoting lymphangiogenesis. In addition, the administration of esaxerenone (a mineralocorticoid receptor blocker, MRB) to rats significantly suppresses this transdifferentiation and alleviates fibrosis. Full article

Background/Objectives: Chronic kidney disease–mineral and bone disorder (CKD-MBD) is characterized by complex interactions between parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), phosphate, calcium, and vitamin D, yet clinical decisions are often based on static individual values. A trajectory-based approach that considers how longitudinal changes in CKD-MBD biomarkers relate to each other may provide a more integrated understanding. Methods: In 1968 adults with non-dialysis CKD (mean age 68 ± 12 years; 34% female; mean follow-up duration 3.02 ± 0.35 years), annualized slopes of CKD-MBD biomarkers (PTH, FGF23, phosphate, calcium) were derived from mixed-effects models, alongside slopes and intra-individual variability of other key features of CKD—eGFR, hemoglobin, albumin, bicarbonate, 25-hydroxyvitamin D, uric acid, urine albumin creatinine ratio (UACR). These 36 features, including baseline levels, were evaluated using Extreme Gradient Boosting regression with interpretability via SHapley Additive exPlanations (SHAP). Results: Models explained substantial variance in biomarker slopes (R²: 0.86 for PTH, 0.72 for FGF23, 0.71 for phosphate, 0.67 for calcium) without evidence of overfitting. Baseline values and eGFR slopes showed the strongest associations with biomarker trajectories. PTH and FGF23 slopes were positively correlated, while declining hemoglobin and greater hemoglobin variability were associated with steeper FGF23 and phosphate slopes. Phosphate slopes were associated with UACR slopes and bicarbonate slopes. Declining 25(OH)D slopes were linked with rising PTH slopes. Conclusions: This analysis revealed consistent relationships between CKD-MBD biomarker trajectories. Longitudinal changes in kidney function, hemoglobin, bicarbonate, UACR, and vitamin D were also associated with biomarker trajectories. Our findings confirm the multi-system nature of CKD-MBD, and provide a framework for examining potentially modifiable pathways in its progression. Full article

Diabetic kidney disease (DKD) remains a primary driver of end-stage kidney disease and cardiovascular morbidity despite the optimized use of renin–angiotensin system (RAS) inhibitors and sodium-glucose cotransporter-2 (SGLT2) inhibitors. Recent evidence identifies the overactivation of the mineralocorticoid receptor (MR) as a critical, independent pathway leading to persistent renal inflammation and fibrosis. In the diabetic milieu, MR overactivation—driven by both aldosterone and ligand-independent factors such as Rac1 GTPase and oxidative stress—triggers pro-inflammatory and pro-fibrotic gene networks. Unlike traditional steroidal mineralocorticoid receptor antagonists (MRAs), the novel non-steroidal MRA finerenone exhibits a distinct binding mode that more effectively blocks the recruitment of transcriptional co-activators, thereby silencing detrimental downstream signaling in podocytes, fibroblasts, and myeloid cells. Preclinical models have demonstrated that MR blockade significantly reduces albuminuria and preserves podocyte integrity independent of systemic blood pressure. These findings translated into landmark clinical trials; the FIDELIO-DKD and FIGARO-DKD trials established that finerenone significantly reduces the risk of kidney disease progression and cardiovascular events across a broad spectrum of chronic kidney disease stages in type 2 diabetes. Furthermore, recent data from the FINEARTS-HF and CONFIDENCE trials suggest a synergetic benefit when combined with SGLT2 inhibitors, offering more robust cardiorenal protection with a manageable risk of hyperkalemia. This review synthesizes the current understanding of MR pathophysiology and clinical evidence, providing a comprehensive framework for the integration of MRAs into the evolving standard of care for patients with diabetic kidney disease. Full article

Candida albicans is a ubiquitous commensal fungus that may be lethal once it gains access to the bloodstream, following a breach in protective barriers such as skin or gut lining. Intravenous injection of C. albicans (4.5 × 10⁴ yeasts/gm of mouse) leads reproducibly to systemic infection with a median survival of about 75 h. We studied the effects of two human innate immune effectors on the course of systemic infections. The soluble human pentraxin serum amyloid P component (hSAP) retards death in murine disseminated candidiasis. In contrast, another soluble pentraxin, human C-reactive protein (hCRP), hastens death. To examine the pathological basis for these differences, necropsies were performed, and the right kidney was removed for study. Candidiasis caused abundant collagen deposition (the precursor to fibrosis) and loss of contrast between the kidney medulla and cortex. Daily administration of subcutaneous hSAP following the intravenous injection of C. albicans preserved the discrete histological difference between cortex and medulla and lessened host collagen deposition. Yeasts and hyphae within abscesses were decorated with hSAP. Contrastingly, kidneys from animals administered C. albicans and hCRP showed extensive collagen deposition and loss of the boundary between the cortex and the medulla of the kidney. hCRP did not bind to fungi but bound to damaged tissue surrounding abscesses, leading to a more destructive infection with loss of tissue. Staining cells with antibodies to CD45 (to detect T-lymphocytes, myelocytes, monocytes, and macrophages) and antibodies to Ly-6G (neutrophils, and granulocytes) showed that hSAP retarded infiltration of inflammatory cells into diseased areas. The results are consistent with the hypothesis that early administration of hSAP represses the migration of inflammatory cells, dampens the production of collagen by fibroblasts, and dampens the overall immune response of the host to infection. In doing so, hSAP prolonged life, whereas hCRP facilitated the infectious process and hastened death. Full article

Upper-tract urothelial carcinoma (UTUC) represents a biologically distinct and clinically challenging subset of urothelial malignancies, accounting for only 5–10% of urothelial cancers but carrying a disproportionately high risk of advanced disease and recurrence. Historically, management strategies for UTUC have been extrapolated from bladder cancer data, with limited prospective evidence specific to the upper urinary tract. However, recent years have witnessed an expanding number of UTUC-focused clinical trials that are reshaping treatment paradigms across localized, locally advanced, and metastatic disease states. This review examines the evolving landscape of clinical trials in UTUC, highlighting pivotal and ongoing studies that will inform contemporary management. We summarize evidence supporting perioperative systemic therapy, including neoadjuvant and adjuvant chemotherapy, and discuss the expanding role of immune checkpoint inhibitors in both perioperative and metastatic settings. Additionally, we review trials evaluating kidney-sparing approaches, intraluminal therapies, and novel drug-delivery platforms aimed at preserving renal function while maintaining oncologic control. Emerging trial designs incorporating molecular profiling, fibroblast growth factor receptor (FGFR)-targeted therapies, and biomarker-driven patient selection are also explored. Despite meaningful progress, significant gaps remain, including the underrepresentation of UTUC patients in large urothelial cancer trials, heterogeneity in risk stratification, and challenges in trial accrual for this rare disease. We conclude by outlining future directions for UTUC-specific clinical research, emphasizing the need for collaborative, multicenter trials, innovative endpoints, and integrated translational studies to further refine personalized treatment strategies. As the clinical trial ecosystem for UTUC continues to mature, these efforts hold promises for improving outcomes while balancing oncologic efficacy with renal preservation. Full article

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) represents a dynamic and multistage pathological process driven by maladaptive intercellular communication. Rather than resulting from isolated cellular injury, AKI-CKD progression unfolds through a spatially and temporally coordinated dysregulation of cellular networks. In the acute phase, damaged tubular epithelial cells act as instigators, releasing damage-associated molecular patterns (DAMPs) and activating a storm of inflammatory crosstalk among immune cells, endothelium, and fibroblasts. During the subacute repair phase, imbalance in macrophage polarization (M1 persistence/M2 dysfunction) and the emergence of senescent tubular cells with a senescence-associated secretory phenotype (SASP) together create a pro-fibrotic microenvironment. In the chronic phase, activated myofibroblasts—derived from multiple sources—establish self-sustaining feedback loops via autocrine signaling, mechanical memory from the stiffened extracellular matrix (ECM), and ongoing dialogue with immune and resident cells, ultimately leading to irreversible fibrosis. Current therapeutic strategies focused on single molecular targets often fail to disrupt this resilient network homeostasis. Therefore, we propose a paradigm shift toward spatiotemporally precise network-remodeling therapies, which require integrated use of liquid biopsy-based staging, smart nanocarriers for cell-specific delivery, and AI-powered multi-omics modeling. This review systematically delineates the evolving cell-to-cell communication networks across AKI-CKD continuum and highlights innovative strategies to intercept disease progression by targeting the pathophysiology of cellular crosstalk. Full article

Chronic kidney disease (CKD) leads to metabolic and cardiovascular complications, and the dysregulation of key biomolecules, namely fibroblast growth factor 23 (FGF23) and Klotho, plays a central role. This study investigated the effects of high-intensity interval training (HIIT) and moderate aerobic training (AT) on FGF23, Klotho, mineral metabolism, apoptosis markers (BAX, Bcl2), and atrial fibrillation (AF) in a rat CKD model. The study used 35 Wistar rats randomly assigned to control (CTL), sham (SH), CKD, CKD + HIIT, and CKD + AT groups. CKD was induced by 5/6 nephrectomy surgery. Exercise interventions consisted of eight weeks of HIIT (80–100% of maximum speed, 24–54 min/week) or AT (45–55% of maximum speed, 40–60 min/week), conducted three times weekly on a treadmill. We measured heart weight, blood levels of FGF23, Klotho, and mineral metabolism markers, as well as the heart expression of apoptosis proteins (i.e., BAX, Bcl2) and atrial fibrillation (AF). Both exercise types reduced the heart weight and heart/body weight ratio; attenuated CKD-induced elevations in FGF23 and reductions in Klotho; improved blood levels of phosphate, PTH, and vitamin D; and modulated apoptotic markers by decreasing BAX and increasing Bcl2 levels. Exercise improved cardiac function and reduced the AF duration. These findings emphasize that exercise could be a helpful non-pharmacological intervention to ameliorate CKD-induced cardiovascular and metabolic disturbances through the modulation of the FGF23 and Klotho pathways. Full article

Cultured urine-derived cells (UDCs) have been proposed as a source of material for the RNA-based molecular diagnosis of genetic disorders. Previous studies have shown that UDCs can be clonally expanded, passaged, frozen, regrown and have some stem cell characteristics, but their anatomic origin and diagnostic utility remain insufficiently explored. In this study, we cultured UDCs from 40 individuals (aged 4 to 20 years; 21 females) and extracted RNA for sequencing. We compared UDC gene expression to that of marker genes of the kidney and urinary tract segments. UDC gene expression most closely matched marker genes of parietal epithelial cells that line the inner surface of Bowman’s capsule in the kidney glomerulus. UDCs expressed VCAM1 (CD106) and POUF51 (OCT4), consistent with a progenitor cell type. UDCs also expressed 54.4% of 3125 OMIM-listed disease-causing genes. This indicated that UDCs can be used to diagnose a similar number of genetic disorders as skin fibroblasts and a wider range of genetic disorders than can be analysed by RNA extracted from whole blood. In conclusion, UDCs are a non-invasive cell source for RNA sequencing that is suitable for investigating a broad range of conditions. Full article

Chemokine CXCL1, also known as Gro-α and MGSA, a ligand of CXCR2, is the best-known CXC chemokine in cancer processes, after CXCL8/IL-8 and CXCL12/SDF-1. This paper is the first review on the role of CXCL1 in general molecular processes associated with cancer. It provides a comprehensive overview that allows for an in-depth understanding of the importance of CXCL1 in tumor-related processes. In this review, however, we did not address the clinical aspects of CXCL1, as these were discussed in our previous review articles. The present paper focuses on the involvement of CXCL1 in cancer processes such as proliferation, cancer stem cell (CSC) function, senescence, angiogenesis, lymphangiogenesis, migration and metastasis, and effects on tumor-associated cells such as neutrophils, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), mesenchymal stem cells (MSCs), and cancer-associated fibroblasts (CAFs). It also describes the significance of CXCL1 in cancer-associated diseases such as cancer cachexia, cancer-associated immunodeficiency, neuroinflammatory-mediated affective-like behaviors, bone cancer pain, and acute kidney injury. We also present the effects of obesity on CXCL1-related cancer processes. Full article

MicroRNAs (miRNAs) are small non-coding RNAs that play central roles in post-transcriptional gene regulation and cellular homeostasis maintenance. Dysregulation of miRNA expression is increasingly recognized as a key contributor to tissue injury during the acute phase and to disease progression in the chronic phase. Chronic kidney disease (CKD) commonly progresses and ultimately leads to kidney failure through interstitial fibrosis, which is the final common pathway of CKD progression. Interstitial fibrosis is driven not only by fibroblast activation but also by phenotypic transitions in injured tubular epithelial cells, infiltrating macrophages, and peritubular capillary cells. These multifaceted cellular pathways induce and exacerbate interstitial fibrosis, and several miRNAs have been identified as important regulators of these pathways. In addition to fibrotic pathophysiological features, disease-specific dysregulation of miRNAs has been increasingly detected in various causes of CKD, including diabetic kidney disease, chronic glomerulonephritis, and nephrosclerosis. In this review, we provide an integrated overview of miRNA-mediated regulation in CKD, with particular emphasis on cell lineage functions within fibrotic pathways and disease-specific roles. Finally, we discuss the emerging potential of miRNAs as biomarkers and therapeutic targets for CKD and highlight future research directions. Full article

Hypertension-induced renal injury is a major cause of chronic kidney disease and end-stage renal disease. Increasing evidence indicates that disease progression is not driven solely by hemodynamic stress but results from the interplay of multiple molecular mechanisms. In this review, we propose a stage-structured and network-based framework to systematically integrate current mechanistic insights into hypertension-induced renal injury. Early events, mainly including endothelial dysfunction and renal hypoxia, establish a permissive microenvironment for disease progression. These insults activate amplifying pathways such as the renin–angiotensin–aldosterone system (RAAS) overactivation, oxidative stress, immune and inflammatory responses, and sympathetic nervous system hyperactivity, which interact through cross-talk and positive feedback loops. Ultimately, these signals converge on fibrotic programs characterized by epithelial–mesenchymal transition (EMT), fibroblast activation, and extracellular matrix deposition, leading to irreversible structural remodeling and functional decline. Furthermore, epigenetics, the gut–kidney axis, autophagy dysfunction and renal aging also contribute to this process. We highlight two critical and underappreciated aspects: the existence of a permissive ‘early-window’ dominated by endothelial dysfunction and hypoxia, which sets the stage for later amplification; and the hierarchical interplay between amplifying mechanisms where cross talk creates self-reinforcing loops that may explain therapeutic resistance. In addition, this review highlights emerging biomarkers for early diagnosis and disease monitoring, and discusses therapeutic advances that extend beyond blood pressure control to disease-modifying interventions that confer renoprotective effects. By integrating molecular mechanisms with diagnostic and therapeutic perspectives, this review provides a comprehensive framework for early detection and precision intervention in hypertension-induced renal injury. Full article

Diabetic kidney disease (DKD) is a major complication of diabetes mellitus that contributes substantially to chronic kidney failure and increased cardiovascular risk. Beyond progressive deterioration of renal function, DKD is associated with disturbances in endocrine and vascular regulation. Among these, alterations in vitamin D homeostasis and blood pressure (BP) control represent clinically relevant, yet incompletely integrated aspects of DKD pathophysiology. This narrative review synthesizes current evidence on the multidirectional relationships between DKD, vitamin D deficiency, and arterial hypertension (AH). Attention is given to renal mechanisms responsible for reduced vitamin D availability in DKD, including proteinuria-related loss of vitamin D-binding proteins, impaired proximal tubular reabsorption, decreased renal activation of vitamin D, and hormonal regulators such as fibroblast growth factor-23. It further discusses how insufficient vitamin D signaling may influence renal and vascular pathways involved in BP regulation. Mechanistic links between vitamin D deficiency and AH in DKD are discussed, with emphasis on maladaptive activation of the renin–angiotensin–aldosterone system (RAAS), persistent inflammation, oxidative stress, endothelial dysfunction, and insulin resistance. These interdependent processes promote both renal injury progression and sustained elevations in BP, forming a self-reinforcing pathogenic loop. Finally, available data on vitamin D-based therapeutic strategies in DKD are reviewed, including native vitamin D supplementation, active vitamin D metabolites, and vitamin D receptor agonists. Although experimental and observational studies suggest potential nephroprotective and vasculoprotective effects, evidence from randomized clinical trials remains heterogeneous. Further well-designed prospective studies are required to clarify the clinical utility of vitamin D interventions in patients with DKD and coexisting AH. Full article

Fibrosis is a hallmark of the tumor microenvironment in many solid cancers, driving tumor progression, immune evasion, and treatment resistance; however, the molecular and cellular mechanisms underlying fibrogenesis—particularly stromal–immune crosstalk across organs—remain incompletely understood, compounded by organ-specific heterogeneity and a lack of reliable immune-related biomarkers. To address this, we performed an integrative single-cell RNA sequencing (scRNA-seq) analysis of fibrotic tissues from four major organs—liver, lung, heart, and kidney—alongside non-fibrotic controls, applying unsupervised clustering, trajectory inference, cell–cell communication modeling, and gene set variation analysis (GSVA) to map the fibro-immune landscape. Our analysis revealed both conserved and organ-specific features: fibroblasts were the dominant extracellular matrix (ECM)-producing cells in liver and lung, whereas endothelial-derived stromal populations prevailed in heart and kidney. Immune profiling uncovered distinct infiltration patterns—macrophages displayed organ-specific polarization states; T cells were enriched for tissue-resident subsets in lung and mucosal-associated invariant T (MAIT) cells in liver; and B cells exhibited marked heterogeneity, including a pathogenic interferon-responsive subset prominent in pulmonary fibrosis. GSVA further identified divergent signaling programs across organs and lineages, including TGF-β/TNF-α in the heart, NOTCH/mTOR in the kidney, glycolysis/ROS in the lung, and KRAS/interferon pathways in the liver. Cell–cell communication analysis highlighted robust crosstalk between macrophages, T/B cells, and stromal cells mediated by collagen, laminin, and CXCL signaling axes. Together, this cross-organ atlas delineates a highly heterogeneous fibro-immune ecosystem in human fibrotic diseases, revealing shared mechanisms alongside organ-specific regulatory networks, with immediate translational implications for precision anti-fibrotic therapy, immunomodulatory drug repurposing, and the development of context-specific biomarkers for clinical stratification and therapeutic monitoring. Full article

Feline chronic kidney disease is a leading cause of mortality in geriatric cats, characterized by a progressive and irreversible loss of renal function. Despite its high prevalence, early diagnosis remains challenging due to nephron compensatory mechanisms and the limited sensitivity of traditional biomarkers, creating a diagnostic gap that necessitates the exploration of novel biomarkers for earlier detection. This review examines the complex pathophysiology of the disease, including renin–angiotensin–aldosterone system activation, tubulointerstitial fibrosis, and mineral metabolism disturbances. By analyzing recent scientific literature, this work evaluates current diagnostic landscape and clinical relevance of emerging biomarkers. Evidence indicates that symmetric dimethylarginine and fibroblast growth factor-23 improve detection of early metabolic and filtration changes, while urinary biomarkers like cystatin B and retinol-binding protein provide specific insights into tubular injury. Bridging the diagnostic gap requires a transition from a reactive, azotemia-based framework to a multi-parametric diagnostic approach that integrates novel biomarkers with serial clinical and laboratory monitoring. Although financial constraints and limited availability restrict widespread clinical implementation, incorporating these advances is essential for earlier prognostic stratification and timely therapeutic decision-making. This integrated strategy has the potential to slow disease progression and improve survival and quality of life in cats with chronic kidney disease. Full article