Podocyte injury and its consequences

Kidney International, Год журнала: 2016, Номер 89(6), С. 1221 - 1230

Опубликована: Март 19, 2016

Podocytes maintain the glomerular filtration barrier, and stability of this barrier depends on their highly differentiated postmitotic phenotype, which also defines particular vulnerability glomerulus. Recent podocyte biology gene disruption studies in vivo indicate a causal relationship between abnormalities single molecules proteinuria glomerulosclerosis. live under various stresses pathological stimuli. They adapt to homeostasis, but excessive stress leads maladaptation with complex biological changes including loss integrity dysregulation cellular metabolism. Podocyte injury causes detachment from basement membrane. In addition "sick" podocytes detachment, our understanding responses following needs address pathways sclerosis. Studies have found variety dysfunction vivo, such as podocyte-endothelial cross talk activation podocyte-parietal cell interactions, all help us understand scenario its consequences. This review focuses aspects adaptive or maladaptive that lead major consequence,

Язык: Английский

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Mechanisms of podocyte injury and implications for diabetic nephropathy

Clinical Science, Год журнала: 2022, Номер 136(7), С. 493 - 520

Опубликована: Апрель 1, 2022

Abstract Albuminuria is the hallmark of both primary and secondary proteinuric glomerulopathies, including focal segmental glomerulosclerosis (FSGS), obesity-related nephropathy, diabetic nephropathy (DN). Moreover, albuminuria an important feature all chronic kidney diseases (CKDs). Podocytes play a key role in maintaining permselectivity glomerular filtration barrier (GFB) injury podocyte, leading to foot process (FP) effacement podocyte loss, unifying underlying mechanism glomerulopathies. The metabolic insult hyperglycemia paramount importance pathogenesis DN, while insults damage are poorly defined other However, shared mechanisms have been identified. Herein, we will review haemodynamic oxidative stress, inflammation, lipotoxicity, endocannabinoid (EC) hypertone, mitochondrial autophagic dysfunction damage, focussing particularly on their DN. Gaining better insight into may provide novel targets for treatment. strategies boosting repair open way regenerative medicine.

Язык: Английский

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LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-β–Induced Angiogenesis

Journal of the American Society of Nephrology, Год журнала: 2019, Номер 30(4), С. 546 - 562

Опубликована: Март 11, 2019

Glomerular endothelial dysfunction and neoangiogenesis have long been implicated in the pathogenesis of diabetic kidney disease (DKD). However, specific molecular pathways contributing to these processes early stages DKD are not well understood. Our recent transcriptomic profiling glomerular cells identified a number proangiogenic genes that were upregulated mice, including leucine-rich α-2-glycoprotein 1 (LRG1). LRG1 was previously shown promote neovascularization mouse models ocular by potentiating TGF-β/activin receptor-like kinase (ALK1) signaling. LRG1's role kidney, particularly setting DKD, has unclear.We analyzed expression mRNA glomeruli kidneys assessed its localization RNA situ hybridization. We examined effects genetic ablation Lrg1 on progression unilaterally nephrectomized, streptozotocin-induced mice at 12 20 weeks after diabetes induction. also whether plasma associated with renal outcome patients type 2 diabetes.LRG1 localized predominantly cells, elevated kidneys. markedly attenuated diabetes-induced angiogenesis, podocyte loss, development glomerulopathy. These improvements reduced ALK1-Smad1/5/8 activation mice. Moreover, increased worse diabetes.These findings identify as potential novel pathogenic mediator risk factor progression.

Язык: Английский

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FoxO3 activation in hypoxic tubules prevents chronic kidney disease

Journal of Clinical Investigation, Год журнала: 2019, Номер 129(6), С. 2374 - 2389

Опубликована: Март 26, 2019

Acute kidney injury (AKI) can lead to chronic disease (CKD) if is severe and/or repair incomplete. However, the pathogenesis of CKD following renal ischemic not fully understood. Capillary rarefaction and tubular hypoxia are common findings during AKI transition. We investigated stress response demonstrated that a responsive transcription factor, FoxO3, was regulated by prolyl hydroxylase. Hypoxia inhibited FoxO3 hydroxylation degradation, thus leading accumulation activation in cells. Hypoxia-activated Hif-1α contributed functioned protect kidneys, as deletion decreased hypoxia-induced activation, resulted more interstitial fibrosis injury. Strikingly, transition aggravated structural functional damage profound phenotype. showed autophagic increased oxidative injury, which may explain protection FoxO3. Our study indicates hypoxic kidney, factors be activated for adaptions counteract insults, attenuating development.

Язык: Английский

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Molecular Mechanisms of Kidney Injury and Repair

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(3), С. 1542 - 1542

Опубликована: Янв. 28, 2022

Chronic kidney disease (CKD) will become the fifth global cause of death by 2040, thus emphasizing need to better understand molecular mechanisms damage and regeneration in kidney. CKD predisposes acute injury (AKI) which, turn, promotes progression. This implies that or AKI-to-CKD transition are associated with dysfunctional repair mechanisms. Current therapeutic options slow progression but fail treat accelerate recovery from AKI unable promote regeneration. Unraveling cellular involved repair, including failure this process, may provide novel biomarkers tools. We now review contribution different events transition, focusing on role macrophages injury, forms regulated cell necroinflammation, senescence senescence-associated secretory phenotype (SAPS), polyploidization, podocyte activation parietal epithelial cells. Next, we discuss key contributors opportunities for their manipulation, a focus resident renal progenitor cells, stem cells reparative secretome, certain macrophage subphenotypes within M2 senescent clearance.

Язык: Английский

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FGF1ΔHBS ameliorates chronic kidney disease via PI3K/AKT mediated suppression of oxidative stress and inflammation

Cell Death and Disease, Год журнала: 2019, Номер 10(6)

Опубликована: Июнь 12, 2019

Abstract Currently, there is a lack of effective therapeutic approaches to the treatment chronic kidney disease (CKD) with irreversible deterioration renal function. This study aimed investigate ability mutant FGF1 (FGF1 ΔHBS , which has reduced mitogenic activity) alleviate CKD and its associated mechanisms. We found that exhibited much weaker activity than wild-type WT ) in tissues. RNA-seq analysis revealed inhibited oxidative stress inflammatory signals mouse podocytes challenged high glucose. These antioxidative anti-inflammatory activities prevented two models: diabetic nephropathy model an adriamycin-induced model. Further mechanistic analyses suggested inhibitory effects on inflammation were mediated by activation GSK-3β/Nrf2 pathway inhibition ASK1/JNK signaling pathway, respectively. An in-depth demonstrated both pathways are under control PI3K/AKT activated . finding expands potential uses for various kinds inflammation.

Язык: Английский

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Single-cell RNA-sequence analysis of mouse glomerular mesangial cells uncovers mesangial cell essential genes

Kidney International, Год журнала: 2017, Номер 92(2), С. 504 - 513

Опубликована: Март 18, 2017

Язык: Английский

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Segmental Sclerosis and Extracapillary Hypercellularity Predict Diabetic ESRD

Journal of the American Society of Nephrology, Год журнала: 2017, Номер 29(2), С. 694 - 703

Опубликована: Ноя. 27, 2017

Pathogenetic markers of diabetic kidney disease (DKD) progression to ESRD are lacking. We characterized the prognostic value histologic findings in DKD for time native specimens from biopsies performed 1995 2011 with glomerulosclerosis as only glomerular diagnosis (n=109). Biopsy were analyzed according standard methods, including determination nephropathy class, defined by Renal Pathology Society. Clinical data extracted electronic medical records. used competing risk models, death risk, estimate subdistribution hazard ratios (HRs) ESRD. All multivariable models included age, sex, black race, baseline eGFR, and proteinuria. Pathologic characteristics achieving P<0.1 added into successively complex models. occurred 56% patients, 26% patients died before reaching In univariate analyses, class was not statistically significant predicting The final model (n=106) showed a borderline association between mild mesangial expansion decreased (subdistribution HR, 0.64; 95% confidence interval, 0.40 1.00). Poor factors segmental sclerosis extracapillary hypercellularity 2.04; 1.36 3.05; 2.21; 1.19 4.11, respectively). conclusion, we identified novel, poor indicators Whether these represent distinct pathogenetic phenotype will require large study broad spectrum severity.

Язык: Английский

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miR-379 deletion ameliorates features of diabetic kidney disease by enhancing adaptive mitophagy via FIS1

Communications Biology, Год журнала: 2021, Номер 4(1)

Опубликована: Янв. 4, 2021

Abstract Diabetic kidney disease (DKD) is a major complication of diabetes. Expression members the microRNA (miRNA) miR-379 cluster increased in DKD. miR-379, most upstream 5′-miRNA cluster, functions endoplasmic reticulum (ER) stress by targeting EDEM3. However, vivo remain unclear. We created knockout (KO) mice using CRISPR-Cas9 nickase and dual guide RNA technique characterized their phenotype screened for targets renal mesangial cells from WT vs. miR-379KO AGO2-immunopreciptation CLASH (cross-linking, ligation, sequencing hybrids) identified redox protein thioredoxin mitochondrial fission-1 protein. were protected features DKD as well body weight loss associated with dysfunction, ER- oxidative stress. These results reveal role metabolic processes via reducing adaptive mitophagy. Strategies could offer therapeutic options

Язык: Английский

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SIRT3-KLF15 signaling ameliorates kidney injury induced by hypertension

Oncotarget, Год журнала: 2017, Номер 8(24), С. 39592 - 39604

Опубликована: Апрель 17, 2017

Renal fibrosis participates in the progression of hypertension-induced kidney injury. The effect SIRT3, a member NAD+-dependent deacetylase family, hypertensive nephropathy remains unclear. In this study, we found that SIRT3 was reduced after angiotensin II (AngII) treatment both vivo and vitro. Furthermore, SIRT3-knockout mice aggravated renal dysfunction via chronic AngII infusion (2000 ng/kg per minute for 42 days). On contrary, SIRT3-overexpression attenuated AngII-induced injury compared with wild-type mice. Remarkably, co-localization KLF15, kidney-enriched nuclear transcription factor, led to directly deacetylating followed by decreased expression fibronectin collagen type IV cultured MPC-5 podocytes. addition, honokiol (HKL), major bioactive compound isolated from Magnolia officinalis (Houpo), suppressed through activating SIRT3-KLF15 signaling. Taken together, our findings implicate novel signaling may prevent hypertension HKL can act as activator protect against nephropathy.

Язык: Английский

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