Abstract:
:Defective cholesterol metabolism primarily linked to reduced ATP-binding cassette transporter A1 (ABCA1) expression is closely associated with the pathogenesis and progression of kidney diseases, including diabetic kidney disease and Alport Syndrome. However, whether the accumulation of free or esterified cholesterol contributes to progression in kidney disease remains unclear. Here, we demonstrate that inhibition of sterol-O-acyltransferase-1 (SOAT1), the enzyme at the endoplasmic reticulum that converts free cholesterol to cholesterol esters, which are then stored in lipid droplets, effectively reduced cholesterol ester and lipid droplet formation in human podocytes. Furthermore, we found that inhibition of SOAT1 in podocytes reduced lipotoxicity-mediated podocyte injury in diabetic kidney disease and Alport Syndrome in association with increased ABCA1 expression and ABCA1-mediated cholesterol efflux. In vivo, Soat1 deficient mice did not develop albuminuria or mesangial expansion at 10-12 months of age. However, Soat1 deficiency/inhibition in experimental models of diabetic kidney disease and Alport Syndrome reduced cholesterol ester content in kidney cortices and protected from disease progression. Thus, targeting SOAT1-mediated cholesterol metabolism may represent a new therapeutic strategy to treat kidney disease in patients with diabetic kidney disease and Alport Syndrome, like that suggested for Alzheimer's disease and cancer treatments.
journal_name
Kidney Intjournal_title
Kidney internationalauthors
Liu X,Ducasa GM,Mallela SK,Kim JJ,Molina J,Mitrofanova A,Wilbon SS,Ge M,Fontanella A,Pedigo C,Santos JV,Nelson RG,Drexler Y,Contreras G,Al-Ali H,Merscher S,Fornoni Adoi
10.1016/j.kint.2020.06.040subject
Has Abstractpub_date
2020-11-01 00:00:00pages
1275-1285issue
5eissn
0085-2538issn
1523-1755pii
S0085-2538(20)30837-1journal_volume
98pub_type
杂志文章abstract::Progressive kidney fibrosis precedes end-stage renal failure in up to a third of patients with diabetes mellitus. Elevated intra-renal transforming growth factor-beta (TGF-beta) is thought to underlie disease progression by promoting deposition of extracellular matrix and epithelial-mesenchymal transition. GW788388 is...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/sj.ki.5002717
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abstract:BACKGROUND:Urea kinetic modeling (UKM) and food records are widely used to assess the dialysis adequacy. Clinicians use these methods in individual patients to decide whether the dialysis prescription should be adjusted. We determined the variation in UKM parameters and dietary intake within individual patients in orde...
journal_title:Kidney international
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1046/j.1523-1755.1999.00412.x
更新日期:1999-05-01 00:00:00
abstract::When patients develop acute kidney injury, a small fraction of them will develop end-stage renal disease later. The severity of renal impairment in the remaining patients is uncertain because studies have not carefully examined renal function over time or the precise timing of entry into a late stage of chronic kidney...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2009.332
更新日期:2009-11-01 00:00:00
abstract::We evaluated the effects of the bisphosphonate pamidronate on bone histomorphometry, structure and strength in male rats with uninephrectomy or with chronic renal disease induced by 5/6 nephrectomy. In rats with chronic renal disease the plasma urea, phosphate and parathyroid hormone levels were significantly increase...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2008.180
更新日期:2008-08-01 00:00:00
abstract::The monoclonal antibody (mAb) 3G5 was found, by indirect immunofluorescence, to bind to renal cortical structures in frozen sections of human, rat and calf kidneys. Double indirect immunofluorescence studies on frozen sections of rat kidneys showed that 3G5 stained only the glomerulus and the distribution of the 3G5 a...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1992.236
更新日期:1992-06-01 00:00:00
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journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2000.00160.x
更新日期:2000-07-01 00:00:00
abstract::Co-presentation with both ANCA and anti-GBM antibodies is thought to be relatively rare. Current studies of such 'double-positive' cases report small numbers and variable outcomes. To study this further we retrospectively analyzed clinical features and long-term outcomes of a large cohort of 568 contemporary patients ...
journal_title:Kidney international
pub_type: 杂志文章,多中心研究
doi:10.1016/j.kint.2017.03.014
更新日期:2017-09-01 00:00:00
abstract::Previous studies have shown that nonsteroidal anti-inflammatory drug (NSAID) use might be associated with a lower risk of developing cancer in the general population. Patients on dialysis have increased risk for cancer, but there are no studies to determine the relationship between NSAID use and cancer risk in these p...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2013.79
更新日期:2013-07-01 00:00:00
abstract::Defects in the primary cilium/basal body complex of renal tubular cells cause polycystic kidney disease (PKD). To uncover pathways associated with disease progression, we determined the kidney transcriptome of 10-day-old severely and mildly affected cpk mice, a model of recessive PKD. In the severe phenotype, the most...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/sj.ki.5002627
更新日期:2008-01-01 00:00:00
abstract::High glucose evokes a variety of signals in mesangial cells that alter cellular functions responsible for the development of diabetic glomerulopathy. The hypoxia-inducible factor-1alpha (HIF-1alpha) regulates cellular homeostasis under hypoxic conditions, but it also has pleiotropic effects in response to cellular str...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2010.99
更新日期:2010-07-01 00:00:00
abstract:BACKGROUND:Microalbuminuria (MA) is a strong predictor of cardiovascular disease, but its causes are incompletely understood. Hyperhomocysteinemia is a recently recognized risk factor for cardiovascular disease independent of established risk factors. It is not known whether hyperhomocysteinemia is associated with MA, ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/sj.ki.4495353
更新日期:1998-07-01 00:00:00
abstract:INTRODUCTION:Thiazide diuretics have the unique characteristic of increasing renal Na+ excretion, while decreasing Ca2+ excretion. However, the molecular mechanism responsible for this thiazide-induced hypocalciuria remains unclear. The present study investigates the effect of thiazides on the expression of the protein...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2003.00128.x
更新日期:2003-08-01 00:00:00
abstract::We compared the effects of calcitriol and doxercalciferol, in combination with either calcium carbonate or sevelamer, on bone, mineral, and fibroblast growth factor-23 (FGF-23) metabolism in patients with secondary hyperparathyroidism. A total of 60 pediatric patients treated with peritoneal dialysis were randomized t...
journal_title:Kidney international
pub_type: 杂志文章,随机对照试验
doi:10.1038/ki.2010.352
更新日期:2011-01-01 00:00:00
abstract::Dihydrotestosterone (DHT) binding studies and the effects of DHT on the expression of beta-glucuronidase (Gus) and kidney androgen-regulated protein (KAP) genes and cell growth were investigated in immortalized early PKSV-PCT and late PKSV-PR proximal tubule cells, derived from transgenic mice carrying the L-pyruvate ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.1998.00721.x
更新日期:1998-01-01 00:00:00
abstract::Prostaglandin E2 (PGE2) may be an important negative feedback modulator of endothelin-1 (ET-1)-stimulated mesangial cell proliferation and contraction. Recent studies suggest that ET-1 may induce prolonged mesangial cell PGE2 production, however the mechanism of this effect is unknown. The current study was undertaken...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1995.6
更新日期:1995-01-01 00:00:00
abstract::Monocyte and macrophage markers are among the most highly overexpressed genes in cpk mouse kidneys with severely progressive renal cystic disease. We show here that one of these markers, CD14, is abnormally transcribed, activated and shed in cystic kidneys. However, these abnormalities were not associated with an incr...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2010.175
更新日期:2010-09-01 00:00:00
abstract::The impact of early-diagnosed new-onset post-transplantation diabetes mellitus (PTDM) on cardiovascular (CV) disease is not well described. The objectives of the present prospective single-center observational study were to assess the long-term effects of early-diagnosed new-onset PTDM on major cardiac events (MCE; ca...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/sj.ki.5000116
更新日期:2006-02-01 00:00:00
abstract::Intrarenal artery infusions of hypertonic saline can activate tubuloglomerular feedback (TGF), decreasing renal blood flow (RBF) and glomerular filtration rate (GFR). The response to infusion of hypertonic saline is enhanced by salt depletion and attenuated by salt loading, but has not previously been investigated in ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.1987.236
更新日期:1987-10-01 00:00:00
abstract::Angiotensin II (Ang II) is a major contributor to the progression of renal fibrosis. Wang and colleagues provide evidence that signaling through the prolyl-4-hydroxylase domain (PHD)-hypoxia-inducible factor-1 (HIF-1) pathway mediates profibrotic effects of Ang II in rat renal medullary interstitial cells under normox...
journal_title:Kidney international
pub_type: 评论,杂志文章
doi:10.1038/ki.2010.434
更新日期:2011-02-01 00:00:00
abstract::The parathyroid hormone response to hypocalcemia was investigated in hemodialysis patients with osteomalacia and compared to those with osteitis fibrosa. Hypocalcemia was induced during hemodialysis by employing a dialysate devoid of calcium. Patients with osteomalacia had a blunted maximum amino terminal parathyroid ...
journal_title:Kidney international
pub_type: 临床试验,杂志文章
doi:10.1038/ki.1983.168
更新日期:1983-09-01 00:00:00
abstract:BACKGROUND:Hypertension is a recognized complication of partial correction of anemia with recombinant human erythropoietin (epoetin) in hemodialysis patients. We used interdialytic ambulatory blood pressure (ABP) monitoring to study the effects of partially corrected anemia versus normal hematocrit (hct) on BP in hemod...
journal_title:Kidney international
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1046/j.1523-1755.1999.00531.x
更新日期:1999-07-01 00:00:00
abstract::We evaluated short- and long-term effects of high-dose recombinant human erythropoietin (rHuEPO) in kidney transplantation in a prospective double-blind, placebo-controlled study. Patients with chronic kidney disease following receipt of a deceased donor kidney allograft were randomized to 3 doses of 40,000 units rHuE...
journal_title:Kidney international
pub_type: 杂志文章,随机对照试验
doi:10.1038/ki.2011.349
更新日期:2012-02-01 00:00:00
abstract:BACKGROUND:In the rat cortical thick ascending limb (CTAL), intracellular Ca2+ ([Ca2+]i) responses to angiotensin II (Ang II) and angiotensin III (Ang III) were mediated by the Ang II subtype 1A receptor (AT1A-R), whereas the arginine vasopressin (AVP)-dependent cAMP accumulation involved the vasopressin receptor type ...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2002.00366.x
更新日期:2002-06-01 00:00:00
abstract:BACKGROUND:Segmental glomerular necrosis has been described in the biopsy material in a minority of patients with idiopathic IgA nephropathy in the oldest studies on this disease, but this marker of active capillaritis has received little attention in the subsequent literature, and its significance and relevance for th...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1046/j.1523-1755.2001.059002682.x
更新日期:2001-02-01 00:00:00
abstract::Acute kidney injury (AKI) following cardiac surgery is closely interrelated with hemodynamic instability and sympathetic activity, and adversely influences prognosis. Here, we investigated in a randomized placebo-controlled trial whether dexmedetomidine, an α2 adrenoreceptor agonist, could prevent AKI after valvular h...
journal_title:Kidney international
pub_type: 杂志文章,随机对照试验
doi:10.1038/ki.2015.306
更新日期:2016-03-01 00:00:00
abstract::Aldosterone exerts its biological effects through binding to mineralocorticoid receptor (MR). Ligand binding induces a receptor transconformation within the ligand-binding domain and dissociation of associated proteins from the receptor. The ligand-activated receptor binds as a dimer to the response elements present i...
journal_title:Kidney international
pub_type: 杂志文章,评审
doi:10.1046/j.1523-1755.2000.00958.x
更新日期:2000-04-01 00:00:00
abstract::Genetic variation at the MYH9 locus is linked to the high incidence of focal segmental glomerulosclerosis (FSGS) and non-diabetic end-stage renal disease among African Americans. To further define risk alleles with FSGS we performed a genome-wide association analysis using more than one million single-nucleotide polym...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2010.251
更新日期:2010-10-01 00:00:00
abstract::Leptin is an adipocyte-derived hormone that acts as a major regulator of food intake and energy homeostasis. It circulates both as a free and as a protein-bound entity. Leptin is released into the blood in proportion to the amount of body fat and exerts sustained inhibitory effects on food intake while increasing ener...
journal_title:Kidney international
pub_type: 杂志文章,评审
doi:10.1038/sj.ki.5000182
更新日期:2006-03-01 00:00:00
abstract::Propofol has been shown to provide protection against renal ischemia/reperfusion injury experimentally, but clinical evidence is lacking. Here we studied the effect of propofol anesthesia on the occurrence of acute kidney injury following heart surgery with cardiopulmonary bypass. One hundred and twelve patients who u...
journal_title:Kidney international
pub_type: 杂志文章,随机对照试验
doi:10.1038/ki.2013.532
更新日期:2014-08-01 00:00:00
abstract::Abnormalities of bone mineral metabolism and vascular calcification are prevalent in patients with kidney failure. Clinical management is based on biochemical targets, in particular parathyroid hormone (PTH) concentrations, but this has many limitations including high biological variation. A possible alternative is bo...
journal_title:Kidney international
pub_type: 杂志文章
doi:10.1038/ki.2012.77
更新日期:2012-07-01 00:00:00