The mitochondrial-targeted peptide, SS-31, improves glomerular architecture in mice of advanced age

Kidney International, Год журнала: 2017, Номер 91(5), С. 1126 - 1145

Опубликована: Янв. 5, 2017

Язык: Английский

---

Organoid single cell profiling identifies a transcriptional signature of glomerular disease

JCI Insight, Год журнала: 2019, Номер 4(1)

Опубликована: Янв. 10, 2019

Podocyte injury is central to many forms of kidney disease, but transcriptional signatures reflecting podocyte and compensation mechanisms are challenging analyze in vivo. Human organoids derived from pluripotent stem cells (PSCs), a potentially new model for disease regeneration, present an opportunity explore the plasticity podocytes. Here, profiling more than 12,000 single human PSC–derived organoid cultures was used identify robust reproducible cell lineage gene expression shared with developing kidneys based on trajectory analysis. Surprisingly, signature characteristic glomerular epithelial also observed tissue cohort. This correlated proteinuria inverse eGFR, it confirmed independent podocytopathy Three genes particular were further characterized as novel components signature. We conclude that reliably recapitulate developmental program podocytes other lineages profiles seen reactivated disease. Our findings demonstrate approach identifying molecular programs involved pathogenesis glomerulopathies.

Язык: Английский

---

Revisiting Experimental Models of Diabetic Nephropathy

International Journal of Molecular Sciences, Год журнала: 2020, Номер 21(10), С. 3587 - 3587

Опубликована: Май 19, 2020

Diabetes prevalence is constantly increasing and, nowadays, it affects more than 350 million people worldwide. Therefore, the of diabetic nephropathy (DN) has also increased, becoming main cause end-stage renal disease (ESRD) in developed world. DN characterized by albuminuria, a decline glomerular filtration rate (GFR), hypertension, mesangial matrix expansion, basement membrane thickening, and tubulointerstitial fibrosis. The therapeutic advances last years have been able to modify delay natural course kidney (DKD). Nevertheless, there still an urgent need characterize pathways that are involved DN, identify risk biomarkers prevent failure patients. Rodent models provide valuable information regarding how set its progression through time. Despite utility these models, depends on diabetes induction method susceptibility each experimental strain. classical murine (Streptozotocin-induced, Akita, or obese type 2 models) do not develop all typical features. For this reason, many crossed susceptible genetic background. Knockout transgenic strains created generate robust models. In review, we will focus description new rodent additionally, overview available methods for phenotyping.

Язык: Английский

---

Dissection of Glomerular Transcriptional Profile in Patients With Diabetic Nephropathy: SRGAP2a Protects Podocyte Structure and Function

Diabetes, Год журнала: 2017, Номер 67(4), С. 717 - 730

Опубликована: Дек. 14, 2017

Podocytes play a pivotal role in maintaining glomerular filtration function through their interdigitated foot processes. However, the mechanisms that govern podocyte cytoskeletal rearrangement remain unclear. Through analyzing transcriptional profile of renal biopsy specimens from patients with diabetic nephropathy (DN) and control donors, we identify SLIT-ROBO ρGTPase-activating protein 2a (SRGAP2a) as one main hub genes strongly associated proteinuria type 2 DN. Immunofluorescence staining Western blot analysis revealed human mouse SRGAP2a is primarily localized at podocytes largely colocalized synaptopodin. Moreover, downregulated DN db/db mice both mRNA level. reduction observed cultured treated tumor growth factor-β or high concentrations glucose. Functional mechanistic studies show suppresses motility inactivating RhoA/Cdc42 but not Rac1. The protective also confirmed zebrafish, which knockdown SRGAP2a, SRGAP2 ortholog recapitulates process effacement. Finally, increasing levels administration adenovirus-expressing significantly mitigates injury proteinuria. results demonstrate protects by suppressing migration.

Язык: Английский

---

Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice

Kidney International, Год журнала: 2017, Номер 92(4), С. 909 - 921

Опубликована: Май 29, 2017

Язык: Английский

---

Autophagy is activated to protect against podocyte injury in adriamycin-induced nephropathy

AJP Renal Physiology, Год журнала: 2017, Номер 313(1), С. F74 - F84

Опубликована: Апрель 13, 2017

Podocytes are highly differentiated epithelial cells wrapping glomerular capillaries to form the filtration barrier in kidneys. As such, podocyte injury or dysfunction is a critical pathogenic event disease. Autophagy plays an important role maintenance of homeostasis and function podocytes. However, it less clear whether how autophagy contributes Here, we have examined adriamycin-induced nephropathy, classic model We show that was induced by adriamycin cultured podocytes vitro mice. In podocytes, activation with rapamycin led suppression apoptosis, whereas inhibition chloroquine enhanced apoptosis during treatment. To determine vivo, established inducible podocyte-specific autophagy-related gene 7 knockout mouse (Podo-Atg7-KO). Compared wild-type littermates, Podo-Atg7-KO mice showed higher levels injury, glomerulopathy, proteinuria Together, these observations support protecting under pathological conditions disease, suggesting therapeutic potential induction.

Язык: Английский

---

FSGS as an Adaptive Response to Growth-Induced Podocyte Stress

Journal of the American Society of Nephrology, Год журнала: 2017, Номер 28(10), С. 2931 - 2945

Опубликована: Июль 18, 2017

Glomerular sclerotic lesions develop when the glomerular filtration surface area exceeds availability of podocyte foot process coverage, but mechanisms involved are incompletely characterized. We evaluated potential using a transgenic (podocin promoter-AA-4E-BP1) rat in which capacity for hypertrophy response to growth factor/nutrient signaling is impaired. FSGS resembling human developed spontaneously by 7 months age, and could be induced earlier accelerating kidney nephrectomy. Early segmental occurred absence detectable reduction average number per glomerulus resulted from loss podocytes individual capillary loops. Parietal epithelial cell division, accumulation on Bowman's capsule, tuft invasion at these sites. Three different interventions that prevented enlargement (calorie intake reduction, inhibition mammalian target rapamycin complex, angiotensin-converting enzyme) protected against lesion development, even initiated late process. Ki67 nuclear staining unbiased transcriptomic analysis identified increased (but not podocyte) cycling as necessary development. The FSGS-associated signature correlated with transcriptomes associated disease progression, compatible similar processes occurring man. conclude development exceeded adapt adequately cover some parts surface. Modest modulation side this equation significantly ameliorated suggesting an underappreciated therapeutic preservation renal function.

Язык: Английский

---

The phenotypes of podocytes and parietal epithelial cells may overlap in diabetic nephropathy

Kidney International, Год журнала: 2015, Номер 88(5), С. 1099 - 1107

Опубликована: Сен. 16, 2015

Язык: Английский

---

Rac1 activation in podocytes induces the spectrum of nephrotic syndrome

Kidney International, Год журнала: 2017, Номер 92(2), С. 349 - 364

Опубликована: Май 6, 2017

Hyper-activation of Rac1, a small GTPase, in glomerular podocytes has been implicated the pathogenesis familial proteinuric kidney diseases. However, role Rac1 acquired nephrotic syndrome is unknown. To gain direct insights into this, we generated transgenic mouse model expressing doxycycline-inducible constitutively active form (CA-Rac1) podocytes. Regardless copy number, proteinuria occurred rapidly within five days, and histology resembled minimal change disease. The degree severity were dependent on transgene number. Upon doxycycline withdrawal, resolved completely (one copy) or nearly (two copy). After one month treatment, two-copy mice developed glomerulosclerosis that focal segmental (FSGS) with urinary shedding transgene-expressing p38 MAPK was activated upon CA-Rac1 induction while inhibitor attenuated proteinuria, podocyte loss, glomerulosclerosis. Mechanistically, activation cultured reduced adhesiveness to laminin induced redistribution β1 integrin, both partially reversed by inhibitor. Activation also seen biopsies from patients disease idiopathic FSGS immunofluorescence sera same human Thus, causes spectrum ranging FSGS, due detachment basement membrane MAPK.

Язык: Английский

---

Profilin1 is required for prevention of mitotic catastrophe in murine and human glomerular diseases

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(24)

Опубликована: Окт. 17, 2023

The progression of proteinuric kidney diseases is associated with podocyte loss but the mechanisms underlying this process remain unclear. Podocytes re-enter cell cycle to repair double-stranded DNA (dsDNA) breaks. However, unsuccessful can result in podocytes crossing G1/S checkpoint and undergoing abortive cytokinesis. In study, we identified Pfn1 as indispensable maintaining glomerular integrity - its tissue-specific mouse results severe proteinuria failure. Our suggest that phenotype due mitotic catastrophe (MC), characterized histologically ultrastructurally by abundant multinucleated cells, irregular nuclei, spindles. Podocyte re-entry was using FUCCI2aR mice observed altered expression cell-cycle proteins such p21, p53, Cyclin B1, D1. Podocyte-specific translating ribosome affinity purification (TRAP) RNAseq revealed downregulation Ribosomal RNA-processing protein 8 (Rrp8). Over-expression Rrp8 KO partially rescued vitro. Clinical ultrastructural tomographic analysis patients diverse further validated presence MC reduction PFN1 within tissues. These profilin1 essential regulating disruption leads subsequent loss.

Язык: Английский

---