Abstract:
:Hyper-activation of Rac1, a small GTPase, in glomerular podocytes has been implicated in the pathogenesis of familial proteinuric kidney diseases. However, the role of Rac1 in acquired nephrotic syndrome is unknown. To gain direct insights into this, we generated a transgenic mouse model expressing a doxycycline-inducible constitutively active form of Rac1 (CA-Rac1) in podocytes. Regardless of the copy number, proteinuria occurred rapidly within five days, and the histology resembled minimal change disease. The degree and severity of proteinuria were dependent on the transgene copy number. Upon doxycycline withdrawal, proteinuria resolved completely (one copy) or nearly completely (two copy). After one month of doxycycline treatment, two-copy mice developed glomerulosclerosis that resembled focal segmental glomerulosclerosis (FSGS) with urinary shedding of transgene-expressing podocytes. p38 MAPK was activated in podocytes upon CA-Rac1 induction while a p38 inhibitor attenuated proteinuria, podocyte loss, and glomerulosclerosis. Mechanistically, activation of Rac1 in cultured mouse podocytes reduced adhesiveness to laminin and induced redistribution of β1 integrin, and both were partially reversed by the p38 inhibitor. Activation of Rac1 in podocytes was also seen in kidney biopsies from patients with minimal change disease and idiopathic FSGS by immunofluorescence while sera from the same patients activated Rac1 in cultured human podocytes. Thus, activation of Rac1 in podocytes causes a spectrum of disease ranging from minimal change disease to FSGS, due to podocyte detachment from the glomerular basement membrane that is partially dependent on p38 MAPK.
journal_name
Kidney Intjournal_title
Kidney internationalauthors
Robins R,Baldwin C,Aoudjit L,Côté JF,Gupta IR,Takano Tdoi
10.1016/j.kint.2017.03.010subject
Has Abstractpub_date
2017-08-01 00:00:00pages
349-364issue
2eissn
0085-2538issn
1523-1755pii
S0085-2538(17)30200-4journal_volume
92pub_type
杂志文章abstract:BACKGROUND:Non-(1-84) parathyroid hormone (PTH) fragments are large circulating carboxyl-terminal (C) fragments with a partially preserved amino-terminal (N) structure. hPTH (7-84), a synthetic surrogate, has been demonstrated to exert biologic effects in vivo and in vitro which are opposite to those of hPTH (1-34) on ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1111/j.1523-1755.2005.00493.x
更新日期:2005-09-01 00:00:00
abstract::Early kidney transplant results in children lagged behind corresponding results in adults. Multiple advances over the past three decades have eliminated that gap. Most children now have equal or superior long-term allograft and patient survival compared with adult recipients. However, black children in the United Stat...
journal_title:Kidney international
pub_type: 评论,杂志文章
doi:10.1038/ki.2014.366
更新日期:2015-03-01 00:00:00
abstract::Simple life-table analyses have not identified the reasons for the steady improvement over the years in graft survival. The use of more sophisticated multifactorial statistical techniques is indicated to identify prognostic factors and to explore the "center effect" on graft survival. An agenda for retrospective analy...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1983.188
更新日期:1983-10-01 00:00:00
abstract:BACKGROUND:We aimed to identify genes with kidney specific, developmentally regulated expression. Here we report the cDNA sequence and expression pattern of KS, a novel kidney-specific rat gene. METHODS:A partial cDNA was identified by differential display polymerase chain reaction (PCR) of a renal cell fraction enric...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.1998.00143.x
更新日期:1998-11-01 00:00:00
abstract::Diabetes is a major cause of chronic kidney disease, and oral antidiabetic drugs are the mainstay of therapy for most patients with Type 2 diabetes. Here we evaluated their role on renal outcomes by using a national Veterans Administration database to assemble a retrospective cohort of 93,577 diabetic patients who fil...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2011.444
更新日期:2012-04-01 00:00:00
abstract::The microcirculation is regulated by oxygen gradients and by endothelial release of nitric oxide, which can react with hemoglobin to form S-nitroso derivatives. Here we induced flow-mediated dilatation of the brachial artery in response to ischemia in 141 non-diabetic patients with stage 3-4 chronic kidney disease who...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2009.63
更新日期:2009-06-01 00:00:00
abstract:BACKGROUND:Middle molecules such as beta2-microglobulin (beta2M) and advanced glycation end products (AGE)-modified proteins contribute to inflammation in uremia. The BetaSorb column is a new adsorptive device, which contains copolymeric beads, suitable for removal of beta2M and other middle molecules. We assessed the ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2003.00839.x
更新日期:2003-03-01 00:00:00
abstract::This study examined the expression of EPO, VEGF and VEGF receptor gene under conditions of reduced oxygen supply in primary cultures of rat hepatocytes, and compared it with the expression of these genes in hypoxic rat livers in vivo. To this end we exposed male Sprague-Dawley rats to hypoxia (10% and 8% O2), carbon m...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1997.60
更新日期:1997-02-01 00:00:00
abstract::Absorption of amino acids by the necturus proximal tubules was measured under free-flow conditions The coexistence of proximal tubular amino acid influx was determined by infusing saline into tubular lumens by the stopped-flow microperfusion technique. Under free-flow conditions, fractional absorption of individual am...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1978.67
更新日期:1978-06-01 00:00:00
abstract:BACKGROUND:Tacrolimus is a relatively new calcineurin inhibitor that has been increasingly used in transplant medicine. The objective of the current work is to report our preliminary experience with tacrolimus in the treatment of diffuse proliferative glomerulonephritis in systemic lupus erythematosus (SLE). METHODS:N...
journal_title:Kidney international
pub_type: 临床试验,杂志文章
doi:10.1111/j.1523-1755.2005.00461.x
更新日期:2005-08-01 00:00:00
abstract::LECT2 amyloidosis is the latest systemic type of amyloidosis to be described. It was discovered in patients with nephrotic syndrome and renal failure and is characterized by amyloid deposition in glomeruli, renal vessels, and interstitium. Clinical and pathological features of earlier phases of this type of amyloidosi...
journal_title:Kidney international
pub_type: 评论,杂志文章
doi:10.1038/ki.2010.18
更新日期:2010-05-01 00:00:00
abstract::The mechanism of the binding of IgA to the mesangium in IgA nephropathy (IgAN) is unknown. Interactions between IgA and components of the mesangial matrix may contribute. We measured by enzyme-linked immunosorbent assay the binding of serum IgA, IgG, and IgM from patients with IgAN, human immunodeficiency virus type I...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1992.298
更新日期:1992-08-01 00:00:00
abstract::Apoptosis mediated by verotoxins (VTs) has been identified in a renal carcinoma cell line, ACHN cells, which are an in vitro model of renal tubular epithelial cells. ACHN cells express the renal tubular marker CD24 as well as globotriaosyl ceramide/CD77, the receptor for VTs. VT binding to the ACHN cell surface was co...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.1998.00939.x
更新日期:1998-06-01 00:00:00
abstract:BACKGROUND:Neointimal hyperplasia occurs commonly at the anastomoses of arteriovenous grafts for chronic hemodialysis, causing stenosis and occlusion. Antiproliferative drugs may be effective in inhibiting hyperplasia, but local drug delivery would be required to minimize systemic side effects. We examined the feasibil...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1111/j.1523-1755.2004.00985.x
更新日期:2004-11-01 00:00:00
abstract::We have studied acid-base balance in 32 patients attending the renal clinic of Mount Sinai Hospital. The parameters of acid-base balance measured included acid production measured as urinary sulfate and organic anions, net acid excretion measured as urinary ammonia plus titratable acid minus bicarbonate, and net GI ab...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1995.79
更新日期:1995-02-01 00:00:00
abstract::Chronic kidney disease (CKD) accelerates muscle protein degradation by stimulating the ubiquitin proteasome system through activation of the E3 ligases, Atrogin-1/MAFbx and MuRF-1. Forkhead transcription factors (FoxOs) can control the expression of these E3 ligases, but the contribution of individual FoxOs to muscle ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2012.84
更新日期:2012-08-01 00:00:00
abstract::Adenosine is known to be a potent inhibitor of renin release from the kidneys. The aim of this study was to investigate the transmembrane signalling avenue that the second messenger of adenosine causes inhibition of renal renin release. Using short term cultures of juxtaglomerular cells isolated from rat kidneys, we f...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1988.70
更新日期:1988-04-01 00:00:00
abstract::The transforming growth factor-beta (TGF-beta) plays a central role in the progression of renal fibrosis. TGF-beta transduces its signal through the activin receptor-like kinase (ALK)5. IN-1130, a novel small molecule ALK5 inhibitor, inhibited the purified kinase domain of ALK5-mediated Smad3 phosphorylation with an I...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/sj.ki.5001775
更新日期:2006-10-01 00:00:00
abstract::Autosomal dominant polycystic kidney disease (ADPKD) is a renal hereditary disorder associated with increased cardiovascular mortality, due to mutations in polycystin-1 and polycystin-2 genes. Endothelial polycystin-deficient cells have an altered mechanosensitivity to fluid shear stress and subsequent deficit in calc...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2014.241
更新日期:2015-02-01 00:00:00
abstract:BACKGROUND:We evaluated the effects of different concentrations of iron dextran administered through the intraperitoneal route, in iron-deficient rats, on hematocrit (Hct in percentage), serum iron (mg/dL), total iron binding capacity (TIBC in mg/dL), and the function and histology of the peritoneal membrane. METHODS:...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2001.059002764.x
更新日期:2001-02-01 00:00:00
abstract::Renal fibrosis is a common pathway leading to the progression of chronic kidney disease, and bone marrow-derived fibroblasts contribute significantly to the development of renal fibrosis. However, the signaling mechanisms underlying the activation of these fibroblasts are not completely understood. Here, we examined t...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1016/j.kint.2017.04.021
更新日期:2017-12-01 00:00:00
abstract::The aging process in humans and in the rat is associated with an impairment in renal tubular reabsorption of Pi and renal tubular adaptation to a low Pi diet. The purposes of the present study were to determine whether changes in the abundance of type II Na-Pi contransporter (NaPi-2) protein and/or mRNA play a role in...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1996.385
更新日期:1996-09-01 00:00:00
abstract::Urinary proteomics is a promising tool for biomarker investigation, particularly in complex kidney diseases. Fabris and colleagues report that urinary laminin subunit alpha-2 is a potential diagnostic marker of medullary sponge kidney (MSK) disease by using a label-free quantitative proteomics platform and a clinicall...
journal_title:Kidney international
pub_type: 评论,杂志文章
doi:10.1016/j.kint.2016.10.032
更新日期:2017-02-01 00:00:00
abstract::The present study was undertaken to: (a) clarify the comparative renal potency of bolus injection of the natriuretic peptides urodilatin and ANF99-126 in the rat; (b) establish whether or not intravenous (i.v.) infusion of urodilatin (200 ng/min) combined with dopamine (UD) to maintain mean arterial pressure could imp...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1992.399
更新日期:1992-11-01 00:00:00
abstract:BACKGROUND:The National Kidney Foundation Dialysis Outcomes Quality Initiative (DOQI) clinical practice guidelines have suggested minimal weekly Kt/V urea and creatinine clearance goals for peritoneal dialysis patients maintained on continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis (APD...
journal_title:Kidney international
pub_type: 临床试验,杂志文章
doi:10.1046/j.1523-1755.2000.00120.x
更新日期:2000-06-01 00:00:00
abstract:UNLABELLED:The paracellular permeability of opossum kidney cells, a proximal tubule cell line. BACKGROUND:The regulation of the unusually leaky paracellular pathway of the proximal tubule is poorly understood partially because of the lack of an appropriate in vitro cell model. In this study, we determined whether the ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.1999.00787.x
更新日期:1999-12-01 00:00:00
abstract::In membranous nephropathy (MN) overproduction of matrix by glomerular epithelial cells (GEC) is believed to be responsible for glomerular basement membrane thickening and spikes. We studied experimental MN in rats (passive Heymann nephritis, PHN) at 5, 10 and 30 days. PHN rats exhibited a marked increase in GEC immuno...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1996.294
更新日期:1996-07-01 00:00:00
abstract:BACKGROUND:An Experimental model of proliferative glomerulonephritis induced by an antibody against Thy-1 antigen has been established. However, the pathophysiologic role and the critical epitope of Thy-1 molecule for induction of mesangial cell dysfunction remain unknown. We have reported that monoclonal antibody 1-22...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1111/j.1523-1755.2004.66011.x
更新日期:2004-12-01 00:00:00
abstract::Utilizing [5-15N] and [2-15N]-labeled glutamine and gas chromatography mass spectrometry methodology, we examined the pathways of ammoniagenesis under basal and acute acidotic conditions of pH 7.0 and pH 6.8, respectively. LLC-PK1 cultures were incubated for one hour with gentle rocking in a bicarbonate buffer of pH 7...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1994.137
更新日期:1994-04-01 00:00:00
abstract::The binding of albumin to the glomerular capillary wall was studied using albumin-gold in perfused kidneys, the interaction of [3H]albumin with isolated glomeruli at 37 degrees C and 4 degrees C and the interaction at [3H]albumin with purified basement membrane. The albumin-gold was found to bind predominantly to the ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1995.149
更新日期:1995-04-01 00:00:00