Abstract:
:Mitochondrial diseases represent a significant clinical challenge. Substantial efforts have been devoted to identifying therapeutic strategies for mitochondrial disorders, but effective interventions have remained elusive. Recently, we reported attenuation of disease in a mouse model of the human mitochondrial disease Leigh syndrome through pharmacological inhibition of the mechanistic target of rapamycin (mTOR). The human mitochondrial disorder MELAS/MIDD (Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes/Maternally Inherited Diabetes and Deafness) shares many phenotypic characteristics with Leigh syndrome. MELAS/MIDD often leads to organ failure and transplantation and there are currently no effective treatments. To examine the therapeutic potential of mTOR inhibition in human mitochondrial disease, four kidney transplant recipients with MELAS/MIDD were switched from calcineurin inhibitors to mTOR inhibitors for immunosuppression. Primary fibroblast lines were generated from patient dermal biopsies and the impact of rapamycin was studied using cell-based end points. Metabolomic profiles of the four patients were obtained before and after the switch. pS6, a measure of mTOR signaling, was significantly increased in MELAS/MIDD cells compared to controls in the absence of treatment, demonstrating mTOR overactivation. Rapamycin rescued multiple deficits in cultured cells including mitochondrial morphology, mitochondrial membrane potential, and replicative capacity. Clinical measures of health and mitochondrial disease progression were improved in all four patients following the switch to an mTOR inhibitor. Metabolomic analysis was consistent with mitochondrial function improvement in all patients.
journal_name
Kidney Intjournal_title
Kidney internationalauthors
Johnson SC,Martinez F,Bitto A,Gonzalez B,Tazaerslan C,Cohen C,Delaval L,Timsit J,Knebelmann B,Terzi F,Mahal T,Zhu Y,Morgan PG,Sedensky MM,Kaeberlein M,Legendre C,Suh Y,Canaud Gdoi
10.1016/j.kint.2018.08.038subject
Has Abstractpub_date
2019-02-01 00:00:00pages
455-466issue
2eissn
0085-2538issn
1523-1755pii
S0085-2538(18)30645-8journal_volume
95pub_type
杂志文章abstract::Human mesangial cells (MC) in culture, when stimulated by interleukin 1 alpha(IL-1 alpha) or tumour necrosis factor (TNF alpha), but not with lipopolysaccharide (LPS), express interleukin 8 (IL-8) mRNA, and both cell associated and extracellular IL-8. Dexamethasone treatment of mesangial cells induced partial inhibiti...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1991.184
更新日期:1991-07-01 00:00:00
abstract::Spontaneous polycystic kidney and liver disease in an inbred herd of Springbok (Antidorcas marsupialis) was studied by light microscopy, transmission electron microscopy, and microdissection. Springbok are a small species of gazelle of the family Bovidae native to South Africa. Since 1976, 18% of all live calves born ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1982.146
更新日期:1982-08-01 00:00:00
abstract::We sought to determine whether artherosclerosis may be accelerated in uremic patients on maintenance hemodialysis and investigated the risk factors for carotid and femoral atherosclerosis in such patients. High-resolution B-mode ultrasonography was used to determine the intima-media thickness (IMT) of the carotid and ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1995.356
更新日期:1995-09-01 00:00:00
abstract::The main distal nephron segment sodium transporters are the distal tubule chlorothiazide-sensitive sodium chloride cotransporter (NCC) and the collecting duct amiloride-sensitive epithelial sodium channel (ENaC). The infusion of ghrelin into the renal interstitium stimulates distal nephron-dependent sodium reabsorptio...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2013.187
更新日期:2013-09-01 00:00:00
abstract::Renal stone disease, which affects 12% of males and 5% of females by the seventh decade, occurs as an inherited disorder in 45% of patients and is most commonly associated with hypercalciuria. The biochemical basis for hereditary nephrolithiasis and hypercalciuria is unknown, and this has therefore been investigated b...
journal_title:Kidney international
pub_type: 杂志文章,评审
doi:10.1046/j.1523-1755.2000.00916.x
更新日期:2000-03-01 00:00:00
abstract:BACKGROUND:Impaired reproductive function accompanies chronic renal insufficiency (uremia) in both the human and experimental animal. Clinical hypogonadism occurs in both genders. The present studies were designed to investigate possible anti-ovulatory effects of uremia in the female rat, a species that produces multip...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2000.00203.x
更新日期:2000-08-01 00:00:00
abstract:UNLABELLED:A non-nucleotide-bridged DNA decoy inhibits renal epithelial nitric oxide synthase expression. BACKGROUND:The expression of inducible nitric oxide synthase (iNOS) is subject to strict tissue-specific transcriptional control. In mouse renal epithelium, an interferon-gamma (IFN-gamma)-induced signaling protei...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2000.00809.x
更新日期:2000-01-01 00:00:00
abstract::X-ray crystal interferometer-based X-ray phase-contrast microtomography (phase-contrast microtomography) is able to image microstructures within soft tissue without the use of a contrast agent. Here we determined the feasibility of using this technique in the non-destructive inspection of formalin-fixed kidney tissue ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2009.42
更新日期:2009-05-01 00:00:00
abstract::Stimulation of interleukin-1 beta (IL-1 beta) and tumor necrosis factor (TNF alpha) production was studied during in vitro hemodialysis (HD) of whole blood using cuprammonium (Cup) or polysulfone (PS) dialyzers. In the absence of LPS, circulation of whole blood for two hours through Cup or PS dialyzers was not suffici...
journal_title:Kidney international
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1038/ki.1990.12
更新日期:1990-01-01 00:00:00
abstract::Peptides representing potential antigenic regions of the NC-1 and 7-S domains of the human alpha 1 and alpha 2, and bovine alpha 3 chains of type IV collagen were synthesized either chemically or by the recombinant DNA technique and tested by ELISA using antibodies raised in rabbits against the whole type IV collagen ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1993.16
更新日期:1993-01-01 00:00:00
abstract::The proportion of deceased donor kidneys procured for transplant but subsequently discarded has been growing steadily in the United States, but factors contributing to the rising discard rate remain unclear. To assess the reasons for and probability of organ discard we assembled a cohort of 212,305 deceased donor kidn...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1016/j.kint.2018.02.016
更新日期:2018-07-01 00:00:00
abstract::The transition between the glomerulus and the proximal tubule was studied by light and electron microscopy in perfusion-fixed rabbit kidneys. In most nephrons a transitional segment of tubule occurred between the Bowman's capsule and the proximal tubule proper. This initial part of the tubule was lined by flattened ce...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1975.22
更新日期:1975-03-01 00:00:00
abstract::Clofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR alpha) agonist, increases renal tubular cytochrome P450 4a (Cyp4a) expression thereby increasing 20-hydroxyeicosatetraenoic acid (20-HETE) production. To determine if clofibrate affects blood pressure regulation we studied mice with DOCA-salt induced...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2008.300
更新日期:2008-10-01 00:00:00
abstract::Recent advances have led to a greater appreciation of how mitochondrial dysfunction contributes to diverse acute and chronic pathologies. Indeed, mitochondria have received increasing attention as a therapeutic target in a variety of diseases because they serve as key regulatory hubs uniquely situated at crossroads be...
journal_title:Kidney international
pub_type: 杂志文章,评审
doi:10.1016/j.kint.2017.05.034
更新日期:2017-11-01 00:00:00
abstract::Although APOL1 high-risk genotype partially accounts for the increased susceptibility of blacks to chronic kidney disease (CKD), whether APOL1 associates differentially with mortality risk remains controversial. Here we evaluate the association between APOL1 genotype and risk of death and determine whether APOL1 statu...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1016/j.kint.2016.09.033
更新日期:2017-02-01 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::Renal blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) is a noninvasive fast technique to characterize renal function. Here we evaluated the impact of renal function on the relaxation rate (R2(*)) in the cortex and medulla to provide baseline data for further use of renal BOLD-MRI. This parameter was...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2011.455
更新日期:2012-04-01 00:00:00
abstract::Recent studies suggest that postnatal neovascularization relies not exclusively on sprouting of preexisting vessels ("angiogenesis"), but also involves the contribution of bone marrow-derived circulating endothelial progenitor cells (EPCs). EPCs can be isolated from peripheral blood or bone marrow mononuclear cells, C...
journal_title:Kidney international
pub_type: 杂志文章,评审
doi:10.1111/j.1523-1755.2005.00261.x
更新日期:2005-05-01 00:00:00
abstract:UNLABELLED:Comparison of treatments for mild secondary hyperparathyroidism in hemodialysis patients. BACKGROUND:In the management of patients with mild secondary hyperparathyroidism, it is not known whether calcium supplementation alone is sufficient to correct abnormalities in bone and mineral metabolism or if calcit...
journal_title:Kidney international
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1046/j.1523-1755.2000.00819.x
更新日期:2000-01-01 00:00:00
abstract::[Arg(8)]-vasopressin (AVP) has several functions via its three distinct receptors, V1a, V1b, and V2. The V1a vasopressin receptor (V1aR) is expressed in blood vessels and involved in vascular contraction. Recently, we generated V1a receptor-deficient (V1aR(-/-)) mice and found that they were hypotensive. In addition, ...
journal_title:Kidney international
pub_type: 杂志文章,评审
doi:10.1038/ki.2009.319
更新日期:2009-11-01 00:00:00
abstract:BACKGROUND:Transforming growth factor-beta (TGF-beta) is known to play an important role in the pathophysiology of renal tubular disease. Researchers have recently identified a novel mitogen-activated protein kinase kinase kinase (MAPKKK), TAK (TGF-beta activated kinase)1, which stimulates the MKK3/6-p38K pathway. The ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.1999.00665.x
更新日期:1999-10-01 00:00:00
abstract::The safety of dietary protein and phosphorous restriction was evaluated in the Modification of Diet in Renal Disease (MDRD) Study. In Study A, 585 patients with a glomerular filtration rate (GFR) of 25 to 55 ml/min/1.73 m2 were randomly assigned to a usual-protein diet (1.3 g/kg/day) or a low-protein diet (0.58 g/kg/d...
journal_title:Kidney international
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1038/ki.1997.395
更新日期:1997-09-01 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 prevalence of cardiovascular disease (CVD) and inflammation is high in patients with end-stage renal disease (ESRD). Adiponectin is an adipocytokine that may have significant anti-inflammatory and anti-atherosclerotic effects. Low adiponectin levels have previously been found in patients with high risk f...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1111/j.1523-1755.2004.00370.x
更新日期:2004-01-01 00:00:00
abstract:BACKGROUND:The renin-angiotensin system has been known to regulate blood pressure and body fluid homeostasis. Several lines of evidence have shown that renin gene expression and release are up-regulated by beta-adrenergic stimulation, sodium depletion, and angiotensin converting enzyme inhibition, but down-regulated by...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.1998.00209.x
更新日期:1998-12-01 00:00:00
abstract:BACKGROUND:Genetic polymorphisms of the angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) genes are associated with increased risk of hypertension and left ventricular hypertrophy (LVH) in hypertensive subjects. However, the extent to which these polymorphisms are related to LVH and remodeling in dialysis p...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2003.00933.x
更新日期:2003-05-01 00:00:00
abstract::Identifying subjects with progressive chronic kidney disease will be important both in clinical practice and in conducting clinical trials. Pruijm et al. (in this issue) demonstrate for the first time that cortical oxygenation as evaluated by blood oxygenation level-dependent magnetic resonance imaging can predict fut...
journal_title:Kidney international
pub_type: 评论,杂志文章
doi:10.1016/j.kint.2017.11.029
更新日期:2018-04-01 00:00:00
abstract::Nephrons possess a segmental organization where each segment is specialized for the secretion and reabsorption of particular solutes. The developmental control of nephron segment patterning remains one of the enigmas within the field of renal biology. Achieving an understanding of the mechanisms that direct nephron se...
journal_title:Kidney international
pub_type: 杂志文章,评审
doi:10.1038/ki.2008.37
更新日期:2008-05-01 00:00:00
abstract::Low nephron number has been related to low birth weight and hypertension. In the southeastern United States, the estimated prevalence of chronic kidney disease due to hypertension is five times greater for African Americans than white subjects. This study investigates the relationships between total glomerular number ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/sj.ki.5000041
更新日期:2006-02-01 00:00:00
abstract::Cell surface aminopeptidases N (APN) and A (APA) have been characterized on cultured human glomerular epithelial cells and a SV40-transformed cell line derived from them. APN had a wide substrate specificity whereas APA only attacked peptides with an acidic N terminal amino acid. Both enzymes also differed by their se...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1992.227
更新日期:1992-06-01 00:00:00