Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex: Implications for renal dysfunction DOI Creative Commons

Jittoku Ihara,

Yibin Huang, Yoichi Takami

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 14, 2024

Abstract Chronic kidney disease (CKD) and atherosclerotic heart disease, frequently associated with dyslipidemia hypertension, represent significant health concerns. We investigated the interplay among these conditions, focusing on role of oxidized low-density lipoprotein (oxLDL) angiotensin II (Ang II) in renal injury via G protein αq subunit (Gq) signaling. hypothesized that oxLDL enhances Ang II-induced Gq signaling AT1 type 1 receptor)-LOX1 (lectin-like receptor) complex. Based CHO cell model experiments, alone did not activate However, when combined II, it significantly potentiated Gq-mediated inositol phosphate production calcium influx cells expressing both LOX-1 but AT1-expressing cells. This suggests a critical synergistic interaction between AT1-LOX1 Conformational studies using biosensors have indicated unique receptor conformational change due to oxLDL-Ang combination. In vivo, wild-type mice fed high-fat diet infusion presented exacerbated dysfunction, whereas knockout not, underscoring pathophysiological relevance damage. These findings highlight novel mechanism dysfunction CKD driven by hypertension suggest therapeutic potential complex patients comorbidities.

Language: Английский

Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging DOI Creative Commons
Gérald J. Prud’homme, Qinghua Wang

Cells, Journal Year: 2024, Volume and Issue: 13(17), P. 1413 - 1413

Published: Aug. 24, 2024

The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia anomalies. Importantly, it associated with chronic pathologies (often age-related) that have inflammatory component. This includes atherosclerosis, diabetes Alzheimer's disease. Its mode of action these diseases not well understood, but inhibits or regulates multiple major pathways. has a membrane form soluble (s-Klotho). Cytosolic postulated characterized. s-Klotho endocrine properties are incompletely elucidated. binds to FGF receptor 1c (FGFR1c) widely expressed (including endothelial cells). also attaches FGF23, FGF23/Klotho FGFRs. Thus, might be roaming FGF23 coreceptor, functions. Notably, (cell-bound soluble) counteracts inflammation appears mitigate related aging (inflammaging). NF-κB NLRP3 inflammasome. inflammasome requires priming by produces active IL-1β, pores cell death (pyroptosis). In accord, countered injury induced toxins, damage-associated molecular patterns (DAMPs), cytokines, reactive oxygen species (ROS). blocks TGF-β Wnt ligands, which lessens fibrotic Low loss muscle mass (sarcopenia), as occurs diseases. counters inhibitory effects myostatin on muscle, reduces inflammation, improves repair following injury. inhibition factors may protective diabetic retinopathy age-related macular degeneration (AMD). review examines functions especially potential applications.

Language: Английский

Citations

10
Anti-Inflammatory Effects of SGLT2 Inhibitors: Focus on Macrophages DOI Open Access

Elena Y. Rykova,

Vadim V. Klimontov, Elena Kazakova

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1670 - 1670

Published: Feb. 15, 2025

A growing body of evidence indicates that nonglycemic effects sodium-glucose cotransporter 2 (SGLT2) inhibitors play an important role in the protective these drugs diabetes, chronic kidney disease, and heart failure. In recent years, anti-inflammatory potential SGLT2 has been actively studied. This review summarizes results clinical experimental studies on activity inhibitors, with a special focus their macrophages, key drivers metabolic inflammation. patients type therapy reduces levels inflammatory mediators. diabetic non-diabetic animal models, control low-grade inflammation by suppressing activation tissue recruitment monocytes from bloodstream, macrophage polarization towards M1 phenotype. The molecular mechanisms macrophages include attenuation inflammasome inhibition TLR4/NF-κB pathway, as well modulation other signaling pathways (AMPK, PI3K/Akt, ERK 1/2-MAPK, JAKs/STAT). discusses state-of-the-art concepts prospects further investigations are needed to obtain deeper insight into underlying molecular, cellular, physiological levels.

Language: Английский

Citations

1
The IL-33-ST2 axis plays a vital role in endometriosis via promoting epithelial–mesenchymal transition by phosphorylating β-catenin DOI Creative Commons

Jingyao Ruan,

Qi Tian,

Siting Li

et al.

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: June 10, 2024

Language: Английский

Citations

5
Role of the epithelial barrier in intestinal fibrosis associated with inflammatory bowel disease: relevance of the epithelial-to mesenchymal transition DOI Creative Commons
Dulce C. Macias-Ceja,

M. Teresa Mendoza-Ballesteros,

María Ortega-Albiach

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: Sept. 26, 2023

In inflammatory bowel disease (IBD), chronic inflammation in the gastrointestinal tract can lead to tissue damage and remodelling, which ultimately result fibrosis. Prolonged injury trigger activation of fibroblasts extracellular matrix (ECM) components. As fibrosis progresses, becomes increasingly stiff less functional, complications such as intestinal strictures, obstructive symptoms, eventually, organ dysfunction. Epithelial cells play a key role fibrosis, they secrete cytokines growth factors that promote fibroblast ECM deposition. Additionally, epithelial undergo process called epithelial-mesenchymal transition, acquire more mesenchymal-like phenotype contribute directly Overall, interactions between cells, immune critical development progression IBD. Understanding these complex may provide new targets for therapeutic interventions prevent or treat this review, we have collected discussed recent literature highlighting contribution pathogenesis fibrotic IBD, including evidence EMT, epigenetic control potential influence microbiome possible strategies target EMT. Finally discuss pro-fibrotic epithelial-immune epithelial-fibroblasts cells.

Language: Английский

Citations

12
Plumbagin ameliorates renal fibrosis by suppressing epithelial-mesenchymal transition DOI

H.-S. Kim,

Ho‐Geun Yoon, Jung‐Yoon Yoo

et al.

Biochemical and Biophysical Research Communications, Journal Year: 2025, Volume and Issue: 750, P. 151325 - 151325

Published: Jan. 13, 2025

Language: Английский

Citations

0
Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex: Implications for renal dysfunction DOI Open Access

Jittoku Ihara,

Yibin Huang, Yoichi Takami

et al.

Published: Jan. 17, 2025

Chronic kidney disease (CKD) and atherosclerotic heart disease, frequently associated with dyslipidemia hypertension, represent significant health concerns. We investigated the interplay among these conditions, focusing on role of oxidized low-density lipoprotein (oxLDL) angiotensin II (Ang II) in renal injury via G protein αq subunit (Gq) signaling. hypothesized that oxLDL enhances Ang II-induced Gq signaling AT1 type 1 receptor)-LOX1 (lectin-like receptor) complex. Based CHO cell model experiments, alone did not activate However, when combined II, it significantly potentiated Gq-mediated inositol phosphate production calcium influx cells expressing both LOX-1 but AT1-expressing cells. This suggests a critical synergistic interaction between AT1-LOX1 Conformational studies using biosensors have indicated unique receptor conformational change due to oxLDL-Ang combination. In vivo, wild-type mice fed high-fat diet infusion presented exacerbated dysfunction, whereas knockout not, underscoring pathophysiological relevance damage. These findings highlight novel mechanism dysfunction CKD driven by hypertension suggest therapeutic potential complex patients comorbidities.

Language: Английский

Citations

0
Pemafibrate ameliorates renal injury through induction of FGF21 and ketone body production in male mice DOI Creative Commons

Kunihiko Takahara,

Noriyuki Ouchi,

Tomonobu Takikawa

et al.

Physiological Reports, Journal Year: 2025, Volume and Issue: 13(3)

Published: Jan. 30, 2025

Abstract Chronic kidney disease is a life‐threatening worldwide. PPARα crucial transcriptional regulator of lipid metabolism and inflammation. Here, we examine whether novel selective modulator, pemafibrate modulates renal injury in model unilateral ureteral obstruction (UUO). Administration to wild‐type (WT) mice led reduction dysfunction fibrosis after UUO with accompanying increases plasma levels fibroblast growth factor (FGF) 21 ketone body β‐hydroxybutyrate (BHB). Treatment WT FGF21 or BHB precursor resulted attenuation fibrotic inflammatory responses UUO. proximal tubular cells reduced expression epithelial–mesenchymal transition markers. These findings suggest that could ameliorate damage, at least part, by its abilities increase the production BHB.

Language: Английский

Citations

0
Dapagliflozin inhibits ferroptosis and ameliorates renal fibrosis in diabetic C57BL/6J mice DOI Creative Commons
Zhen Zhang, Luxin Li,

Yucen Dai

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 28, 2025

Diabetic nephropathy (DN) is a common complication of diabetes and major cause end-stage renal disease, with complex pathogenesis involving inflammation, oxidative stress, fibrosis, ferroptosis. Ferroptosis linked to DN progression, yet treatment options are limited, particularly for targeting Dapagliflozin (DAPA), an SGLT2 inhibitor, shows protective effects in diabetes, but its role fibrosis ferroptosis unclear. This study investigated DAPA's effect on by inhibiting ferroptosis, using streptozotocin-induced diabetic mouse model. Results indicated that DAPA improved function, reduced suppressed markers mice. In vitro, inhibited HK-2 cells under high glucose conditions. Molecular docking network pharmacology suggested anti-fibrotic anti-ferroptotic may involve the Nrf2 TGF-β signaling pathways. also serum creatinine blood urea nitrogen mice, glomerulosclerosis interstitial decreased iron deposition, enhanced antioxidant activity. Overall, multi-target mechanisms significantly improve suggesting potential as targeted therapy against Future studies should further explore applications.

Language: Английский

Citations

0
Effects of calciprotein particles on EMT induction in an in vitro 3D‐cultured proximal tubule epithelial cell model of CKD DOI Open Access

Yeo Min Yoon,

Sang‐Mi Woo,

Hwanuk Guim

et al.

BioFactors, Journal Year: 2025, Volume and Issue: 51(2)

Published: March 1, 2025

Calciprotein particles (CPPs) are blood-borne circulating nanoparticles composed of calcium phosphate and proteins that known to exacerbate pathological processes such as chronic kidney disease-mineral bone disorder (CKD-MBD). Despite the significant interest in CKD-MBD pathogenesis, research directly addressing CPP-induced fibrosis renal proximal tubules is rare, largely owing lack suitable vitro tissue models. Our study confirmed 3D-cultured tubule epithelial cells (PTECs) exhibited enhanced characteristics compared 2D-cultured PTECs when treated with CPPs, a key factor CKD-MBD, uremic toxin. under CKD-inducing conditions by CPPs were associated epithelial-mesenchymal transition (EMT), mediated transforming growth factor-β1 (TGF-β1), notable changes early EMT marker expression. Furthermore, this was attributed increased expression calcium-sensing receptor (CASR), for activation downstream cell division control protein 42 (CDC42), leading progression. This underscores potential PTEC-on-a-chip systems serve drug testing models, given heightened sensitivity these external environments. approach provides better understanding features CKD could contribute development more effective models therapeutics.

Language: Английский

Citations

0
Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex DOI Creative Commons

Jittoku Ihara,

Yibin Huang, Yoichi Takami

et al.

eLife, Journal Year: 2025, Volume and Issue: 13

Published: March 25, 2025

Chronic kidney disease (CKD) and atherosclerotic heart disease, frequently associated with dyslipidemia hypertension, represent significant health concerns. We investigated the interplay among these conditions, focusing on role of oxidized low-density lipoprotein (oxLDL) angiotensin II (Ang II) in renal injury via G protein αq subunit (Gq) signaling. hypothesized that oxLDL enhances Ang II-induced Gq signaling AT1 type 1 receptor)-LOX1 (lectin-like receptor) complex. Based CHO cell model experiments, alone did not activate However, when combined II, it significantly potentiated Gq-mediated inositol phosphate production calcium influx cells expressing both LOX-1 but AT1-expressing cells. This suggests a critical synergistic interaction between AT1-LOX1 Conformational studies using biosensors have indicated unique receptor conformational change due to oxLDL-Ang combination. In vivo, wild-type mice fed high-fat diet infusion presented exacerbated dysfunction, whereas knockout not, underscoring pathophysiological relevance damage. These findings highlight novel mechanism dysfunction CKD driven by hypertension suggest therapeutic potential complex patients comorbidities.

Language: Английский

Citations

0