The cellular and molecular mechanisms of EndMT relevant to CKD are summarized, key regulatory pathways and pathway crosstalk are highlighted, and emerging pharmacological approaches to limit EndMT, preserve microvascular integrity, and attenuate renal fibrogenesis are discussed.
Cardiac fibrosis is a central pathological feature of many cardiovascular diseases and contributes to progressive myocardial remodeling and heart failure. Among the diverse cellular sources of activated fibroblasts, endothelial cells have emerged as a significant contributor through endothelial-to-mesenchymal transition (EndMT). During EndMT, endothelial cells lose their endothelial characteristics and acquire mesenchymal phenotypes, resulting in increased extracellular matrix deposition and tissue stiffening. Multiple pathological stimuli, including inflammatory signaling, oxidative stress, and metabolic dysregulation, activate intracellular signaling pathways that drive EndMT. In addition to these molecular mechanisms, recent studies highlight the importance of intercellular communication mediated by extracellular vesicles, particularly exosomes carrying microRNAs (miRNAs), in regulating cardiac fibrosis. Exosomal miRNAs released from endothelial cells, cardiomyocytes, and fibroblasts can modulate fibrotic signaling networks and influence EndMT progression. This review summarizes the pathological signaling pathways governing EndMT in cardiac fibrosis and discusses the emerging roles of exosomal miRNA-mediated crosstalk in cardiac remodeling. Understanding these integrated mechanisms may provide new insights into therapeutic strategies targeting cardiac fibrosis.
Lan Phuong Phan, Kyung-Sun Heo· Korean Journal of Physiology...· 0 citations
Endothelial-to-Mesenchymal Transition (EndMT) is a significant contributor to Blood- Brain Barrier (BBB) dysfunction in various brain diseases. The majority of current therapies, aimed at reducing BBB dysfunction, focus on preventing inflammation or stabilizing tight junctions. In most cases, these therapies do not provide adequate or long-lasting vascular protection. Endothelial cells undergo phenotypic programming, losing their barrier-forming capacity and developing features of mesenchymal and extracellular matrix-producing cells as the disease progresses. The change leads to chronic vascular leakage, neuroinflammation, microvascular fibrosis, and dysfunctional neurovascular coupling. Several upstream stimuli, including inflammatory cytokines, TGF-β/BMP-Smad signaling, and oxidative damage, converge to drive EndMT within the distinctive, specialized environment of the brain endothelium. Ischemic stroke, multiple sclerosis, cerebral cavernous malformations, arteriovenous malformations, glioblastoma, brain metastasis, and Alzheimer's disease indicate that EndMT is not a rare or unique process but a shared and common pathologic process that may result in disease progression and eventual resistance to treatment. Recent single-cell and spatial transcriptomic data have shown that partial EndMT states exist and may be precursors to irreversible microvascular remodeling. It is necessary to identify therapeutic approaches that go beyond short-term stabilization of the BBB and target the molecular programs underlying the loss of endothelial identity. This review synthesizes mechanistic, disease-related, and therapeutic evidence indicating that EndMT is a leading cause of BBB failure and highlights therapeutic opportunities for targeting this endothelial plasticity in brain diseases.
Nur Iffah Ishak, R. Siran, Wan Nor I’zzah Wan Mohamad Zain et al.· CNS and Neurological Disorde...· 0 citations
Chronic kidney disease is a global health concern characterized by maladaptive repair processes leading to kidney fibrosis. Following injury, early alterations in the extracellular matrix precede the development of kidney fibrosis and represent potential therapeutic targets to improve kidney repair. In this context, studies from our laboratory and others have shown that the matricellular protein SMOC2 can be targeted to decrease inflammation and tubulointerstitial fibrosis following kidney injury. The tubular epithelial cells (TECs), which are abundant and particularly susceptible to injury, play a central role in maladaptive repair; however, whether SMOC2 affects their functionality after kidney injury has not been explored. In this study, we show that SMOC2 localizes to the basement membrane of injured TECs across three murine models of kidney injury. Our in vitro studies demonstrate that SMOC2 induces a partial epithelial-to-mesenchymal (EMT) transition of TECs. We further demonstrate that its extracellular calcium-binding domain mediates binding to the decellularized extracellular matrix and mediates most of its effects on TECs. Mechanistically, SMOC2 promotes partial EMT effects through an integrin-dependent pathway. Together, these findings provide new mechanistic insight into how SMOC2 drives maladaptive repair by modulating TEC behavior and identify its calcium-binding domain as a key functional mediator.
Background: Diabetic kidney disease (DKD) remains a
major cause of end-stage renal disease worldwide, yet
current clinical biomarkers such as albuminuria and estimated glomerular filtration rate lack sufficient sensitivity
to detect early renal injury or predict individual disease
trajectories. Growth differentiation factor 15 (GDF15), a
stress-inducible cytokine belonging to the transforming
growth factor-b superfamily, has emerged as a promising
molecular link between metabolic stress, inflammation,
mitochondrial dysfunction, and renal injury in diabetes.
This review systematically synthesizes current experimental and clinical evidence on the role of GDF15 in
DKD, with emphasis on its mechanistic involvement in
renal pathophysiology and its translational potential as
a biomarker and therapeutic target. Evidence from preclinical models and human studies indicates that GDF15
is upregulated in diabetic kidneys, particularly in tubular
epithelial cells, in response to hyperglycemia-induced
oxidative stress and mitochondrial dysfunction. Mechanistically, GDF15 modulates key pathogenic pathways in
DKD, including NF-kB–mediated inflammation, NLRP3
inflammasome activation, macrophage polarization,
TGF-b/Smad-driven fibrogenesis, and autophagy regulation through PI3K/Akt and AMPK signaling. Clinically, circulating and urinary GDF15 levels correlate with disease
severity and independently predict renal function decline,
suggesting utility in both early diagnosis and prognostic stratification. In addition, emerging evidence supports its
potential role as a pharmacodynamic marker responsive
to interventions such as metformin and SGLT2 inhibitors.
However, its context-dependent biological effects, lack
of assay standardization, and confounding elevation in
systemic diseases remain key challenges. Overall, GDF15
represents a central stress-integrating mediator in DKD
pathogenesis and a promising candidate for precision
nephrology, warranting further validation in longitudinal
multi-omics and interventional studies.
Yu Chen, Min Li, Min Yang et al.· Journal of Medical Biochemis...· 0 citations
This review examines emerging mechanisms that govern kidney fibrogenesis, with emphasis on therapeutic tractability, and considers how experimental models can improve target prioritization and drug development, and summarizes repurposed drugs, pathway-targeted agents, receptor-directed strategies and cell-based approaches under preclinical or clinical evaluation.
Kidney fibrosis is the pathologic hallmark of chronic kidney disease (CKD) and is driven by fibroblast-to-myofibroblast transformation (FMT), excessive extracellular matrix accumulation, and persistent activation of transforming growth factor-β (TGFβ) signaling. Although TGFβ is a central mediator of fibrosis, its pleiotropic physiological functions have limited the development of direct anti-fibrotic therapies, highlighting the need to identify context-specific regulators of this pathway. Matrix Gla Protein (MGP) is a vitamin K-dependent extracellular protein best known for inhibiting vascular calcification; however, its role in kidney fibrosis remains unknown. Here, we demonstrate that MGP expression is markedly upregulated in fibroblasts from fibrotic kidneys in mouse models of chronic kidney injury and in human CKD samples. Using inducible global and fibroblast-specific Mgp knockout mice, we show that Mgp deficiency attenuates renal fibrosis, suppresses fibroblast activation, and preserves kidney function following folic acid nephropathy and unilateral ureteral obstruction. Mechanistically, MGP promotes FMT and amplifies TGFβ receptor/Smad3 signaling, whereas genetic or molecular inhibition of MGP blunts TGFβ-driven fibroblast activation both in vivo and in vitro. We further identify phosphorylation and γ-carboxylation as essential post-translational modifications required for the profibrotic activity of MGP. In addition, MGP interacts with bone morphogenetic protein-2 (BMP-2), reduces BMP-2 protein abundance, and counteracts BMP-2-mediated suppression of TGFβ signaling, thereby enhancing profibrotic responses. Collectively, these findings identify MGP as a previously unrecognized regulator of TGFβ-dependent fibroblast activation and kidney fibrosis, supporting MGP as a potential fibroblast-associated target for future strategies aimed at limiting CKD progression.
Jonatan Barrera-Chimal, J. López-Ramirez, Nathalie Henley et al.· Molecular Biomedicine· 0 citations
