GLP-1 and glucagon receptor dual agonism ameliorates kidney allograft fibrosis by improving lipid metabolism DOI Creative Commons
Linjie Peng,

Weijie Lai,

Shuangjin Yu

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 31, 2025

Kidney allograft fibrosis accelerates the progression of chronic kidney disease (CKD), leads to failure, and increases patient mortality. Emerging evidence suggests that metabolic syndrome in transplant recipients is associated with development. However, it remains unclear whether targeting pathways can mitigate fibrosis. This study aimed explore potential using GLP-1R/GCGR dual agonist TB001 for treatment was induced rat models. Histological analysis, transcriptome sequencing, vitro experiments were performed investigate efficacy its underlying mechanisms. Compared control group, TB001-treated had significantly improved function, as evidenced by lower creatinine 24-hour urine protein levels. Moreover, decreased body weight serum total cholesterol, LDL-cholesterol, TNF-α levels recipients, indicating improvements. Pathological analysis demonstrated reduced inflammatory cell infiltration downregulated expression markers, including TGF-β1, α-SMA, COL1A1, Vimentin. Further sequencing grafts revealed group a gene pattern similar syngeneic showed significant enhancement lipid metabolism-related pathways, particularly PPAR pathway. In vivo further upregulated CPT1A, key molecule involved metabolism, inhibited TGF-β1/Smad2/3/Twist PKC-α/PKC-β pathways. Targeting shows managing

Language: Английский

Cellular and molecular mechanisms of kidney fibrosis DOI
Sonja Djudjaj, Peter Boor

Molecular Aspects of Medicine, Journal Year: 2018, Volume and Issue: 65, P. 16 - 36

Published: June 22, 2018

Language: Английский

Citations

379
Macrophage-to-Myofibroblast Transition Contributes to Interstitial Fibrosis in Chronic Renal Allograft Injury DOI Open Access
Yingying Wang, Hong Jiang, Jun Pan

et al.

Journal of the American Society of Nephrology, Journal Year: 2017, Volume and Issue: 28(7), P. 2053 - 2067

Published: Feb. 16, 2017

Interstitial fibrosis is an important contributor to graft loss in chronic renal allograft injury. Inflammatory macrophages are associated with allografts, but how these cells contribute this damaging response not clearly understood. Here, we investigated the role of macrophage-to-myofibroblast transition interstitial human and experimental In biopsy specimens from patients active rejection, identified undergoing by coexpression macrophage (CD68) myofibroblast (α-smooth muscle actin [α-SMA]) markers. CD68+/α-SMA+ accounted for approximately 50% population, number correlated function severity fibrosis. Similarly, C57BL/6J mice a BALB/c allograft, coexpressing markers (CD68 or F4/80) α-SMA composed significant population interstitium allografts rejection. Fate-mapping Lyz2-Cre/Rosa26-Tomato showed that half α-SMA+ myofibroblasts originated recipient bone marrow-derived macrophages. Knockout Smad3 protected against substantially reduced cells. Furthermore, majority rejection coexpressed M2-type marker CD206, expression was considerably Smad3-knockout recipients. conclusion, our studies indicate contributes Moreover, regulated via Smad3-dependent mechanism.

Language: Английский

Citations

321
Extracellular Matrix in Kidney Fibrosis: More Than Just a Scaffold DOI Open Access
Roman D. Bülow, Peter Boor

Journal of Histochemistry & Cytochemistry, Journal Year: 2019, Volume and Issue: 67(9), P. 643 - 661

Published: May 22, 2019

Kidney fibrosis is the common histological end-point of progressive, chronic kidney diseases (CKDs) regardless underlying etiology. The hallmark renal fibrosis, similar to all other organs, pathological deposition extracellular matrix (ECM). Renal ECM a complex network collagens, elastin, and several glycoproteins proteoglycans forming basal membranes interstitial space. Several functions beyond providing scaffold organ stability are being increasingly recognized, for example, in inflammation. composition determined by function each compartments kidney, that is, glomeruli, tubulo-interstitium, vessels. dynamic structure undergoing remodeling, particularly during fibrosis. From clinical perspective, proteins directly involved rare indirectly CKD progression could serve as specific non-invasive biomarkers scaffolds regenerative medicine. gold standard currently only means measure biopsy, but new diagnostic approaches appearing. Here, we discuss localization, function, remodeling major components healthy diseased, fibrotic kidneys potential use diagnostics tissue engineering.

Language: Английский

Citations

297
Rediscovering Beta-2 Microglobulin As a Biomarker across the Spectrum of Kidney Diseases DOI Creative Commons
Christos Argyropoulos,

Shan Shan Chen,

Yue‐Harn Ng

et al.

Frontiers in Medicine, Journal Year: 2017, Volume and Issue: 4

Published: June 15, 2017

There is currently an unmet need for better biomarkers across the spectrum of renal diseases. In this paper, we revisit role beta-2 microglobulin (β2M) as a biomarker in patients with chronic kidney disease and end-stage disease. Prior to reviewing numerous clinical studies area, describe basic biology β2M, focusing particular on its maintaining serum albumin levels reclaiming tubular fluid through actions neonatal Fc receptor. Disorders abnormal β2M function arise result altered binding protein cofactors manifestations are exemplified by rare human genetic conditions mice knockouts. We highlight utility predictor outcomes recent large database against predictions made recently developed whole body population kinetic models. Furthermore, discuss animal data suggesting that contrary textbook dogma urinary may be marker glomerular rather than pathology. review existing literature about receiving replacement therapy, emphasis outcome trials. note emerging proteomic promising allograft nephropathy. Finally, present number non-renal The goal comprehensive direct attention multifaceted biomarker, exciting order propose next steps required bring rediscovered into twenty-first century.

Language: Английский

Citations

246
Renal tubular epithelial cells: the neglected mediator of tubulointerstitial fibrosis after injury DOI Creative Commons
Ruochen Qi, Cheng Yang

Cell Death and Disease, Journal Year: 2018, Volume and Issue: 9(11)

Published: Nov. 13, 2018

Abstract Renal fibrosis, especially tubulointerstitial is the inevitable outcome of all progressive chronic kidney diseases (CKDs) and exerts a great health burden worldwide. For long time, interests in renal fibrosis have been concentrated on fibroblasts myofibroblasts. However, recent years, growing numbers studies focused role tubular epithelial cells (TECs). TECs, rather than victim or bystander, are probably neglected mediator responding to variety injuries. The maladaptive repair mechanisms TECs may be key point this process. In review, we will focus fibrosis. We follow fate cell depict intracellular changes after injury. then discuss how mechanism becomes maladaptive, finally intercellular crosstalk interstitium that ultimately proceeds

Language: Английский

Citations

201
Iron accumulation drives fibrosis, senescence and the senescence-associated secretory phenotype DOI Creative Commons
Máté Maus, Vanessa López-Polo, Lídia Mateo

et al.

Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(12), P. 2111 - 2130

Published: Dec. 14, 2023

Abstract Fibrogenesis is part of a normal protective response to tissue injury that can become irreversible and progressive, leading fatal diseases. Senescent cells are main driver fibrotic diseases through their secretome, known as senescence-associated secretory phenotype (SASP). Here, we report cellular senescence, multiple types in mice humans characterized by the accumulation iron. We show vascular hemolytic injuries efficient triggering iron accumulation, which turn cause senescence promote fibrosis. Notably, find senescent persistently accumulate iron, even when surge extracellular has subdued. Indeed, under conditions exposed different senescence-inducing insults abundant ferritin-bound mostly within lysosomes, present high levels labile fuels generation reactive oxygen species SASP. Finally, demonstrate detection magnetic resonance imaging might allow non-invasive assessment burden kidneys patients with renal Our findings suggest plays central role fibrosis, initiating events may be independent identify metabolism potential therapeutic target for

Language: Английский

Citations

75
Epithelial–mesenchymal transition in tissue repair and degeneration DOI
Khalil Kass Youssef, M. Ángela Nieto

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(9), P. 720 - 739

Published: April 29, 2024

Language: Английский

Citations

25
Molecular assessment of disease states in kidney transplant biopsy samples DOI
Philip F. Halloran, Konrad S. Famulski, J. Reeve

et al.

Nature Reviews Nephrology, Journal Year: 2016, Volume and Issue: 12(9), P. 534 - 548

Published: June 27, 2016

Language: Английский

Citations

158
Treatment of Renal Fibrosis—Turning Challenges into Opportunities DOI
Barbara M. Klinkhammer, Roel Goldschmeding, Jürgen Floege

et al.

Advances in Chronic Kidney Disease, Journal Year: 2017, Volume and Issue: 24(2), P. 117 - 129

Published: March 1, 2017

Language: Английский

Citations

138
Protocol of a randomised controlled, open-label trial of ex vivo normothermic perfusion versus static cold storage in donation after circulatory death renal transplantation DOI Creative Commons
Sarah A. Hosgood, Kourosh Saeb‐Parsy, Colin Wilson

et al.

BMJ Open, Journal Year: 2017, Volume and Issue: 7(1), P. e012237 - e012237

Published: Jan. 1, 2017

Ex vivo normothermic perfusion (EVNP) is a novel technique that reconditions the kidney and restores renal function prior to transplantation. Phase I data from series of EVNP in extended criteria donor kidneys have established safety feasibility clinical practice.This UK-based phase II multicentre randomised controlled trial assess efficacy compared with conventional static cold storage donation after circulatory death (DCD) 400 patients receiving DCD (categories III IV, controlled) will be recruited into study. On arrival at transplant centre, receive either (n=200) or remain (n=200). Kidneys undergoing perfused an oxygenated packed red cell solution near body temperature for 60 min The primary outcome measure determined by rates delayed graft (DGF) defined as need dialysis first week post-transplant. Secondary measures include incidences non-function, duration DGF, functional DGF <10% fall serum creatinine 3 consecutive days post-transplant, reduction ratio 2 5, length hospital stay, biopsy-proven acute rejection, estimated glomerular filtration rate 1, 3, 6 12 months post-transplant patient allograft survival. assessment score recorded level fibrosis inflammation also measured using tissue, blood urine samples. Ethics dissemination. study has been approved National Health Service (NHS) Research Authority Committee. results are expected published 2020.ISRCTN15821205; Pre-results.

Language: Английский

Citations

133