Acute Tubular Injury Causes Dysregulation of Cellular Cholesterol Transport Proteins

Zager, Richard A.; Johnson, Ali C. M.; Hanson, Sherry Y.; Shah, Vallabh O.

doi:10.1016/s0002-9440(10)63655-3

Cited by 34 publications

(43 citation statements)

References 37 publications

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“…Although much of the research to date into the role of LXR␣ in the kidney has been centered on the mesangium and glomerulus, it is increasingly recognized that pathology within the tubulointerstitium is ultimately more predictive of the renal outcome (45). Indeed, in the diverse forms of acute renal injury, including the sepsis syndrome, both free cholesterol and cholesteryl esters accumulate within the proximal tubular epithelium (46)(47)(48)(49)(50). It has been suggested that PTC cholesterol accumulation is an integral component of the kidney's response to tissue injury, so that PTCs increase resistance to superimposed nephrotoxic attack and thus acquire cytoresistance (48,49,51).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of liver X receptor-α in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines

Wang

Moser

Shigenaga

et al. 2005

Journal of Lipid Research

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Infection and inflammation induce the acute-phase response (APR), which leads to dramatic alterations in lipid and lipoprotein metabolism (1, 2). Hypertriglyceridemia (3, 4), decreased high density lipoprotein cholesterol levels (5, 6), enhanced lipolysis, and decreased fatty acid oxidation (7, 8) are some of the changes that are often observed during the APR. These alterations in lipoprotein metabolism are believed to confer immediate protection to the host from further detrimental damage during the acute stage of infection (1, 2). In many instances, these metabolic alterations are attributable to increased or decreased transcription of genes that control lipid metabolism, and they are often induced by proinflammatory cytokines such as tumor necrosis factor (TNF) or interleukin-1 (IL-1) (1, 2). Although the underlying mechanisms remain to be identified, we and others have shown that cytokine-induced suppression of many lipid genes during the APR is achieved through the downregulation of type II nuclear hormone receptors (9-13).Several nuclear hormone receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and farnesoid X receptor (FXR), belong to the type II receptor superfamily (14). These receptors bind to DNA as obligate heterodimers with the retinoid X receptor (RXR) (15). Unlike the steroid receptors that shuttle between the cytoplasm and the nucleus, most RXR heterodimers are constitutively in the nucleus. In the absence of ligand, the heterodimers are believed to be bound to DNA and complexed with corepressor proteins. Ligand binding induces a structural change that dissociates the corepressor proteins, recruits the coactivator proteins, and promotes the transcription of target genes (16).Among these nuclear hormone receptors, LXR plays an important role in regulating the transcription of genes responsible for cholesterol metabolism and homeostasis, in-

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Section: Discussionmentioning

confidence: 99%

Downregulation of liver X receptor-α in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines

Wang

Moser

Shigenaga

et al. 2005

Journal of Lipid Research

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“…In fact, accumulation of lipids in the renal tissue has been implicated in the progression of glomerular and tubulointerstitial lesions in metabolic syndrome (1,38) and chronic glomerulopathies (24,48). Similarly, accumulation of cholesterol in proximal tubular epithelial cells participates in the pathogenesis of acute kidney injury in animals with experimental rhabdomyolysis (60).…”

mentioning

confidence: 99%

Renal mass reduction results in accumulation of lipids and dysregulation of lipid regulatory proteins in the remnant kidney

Kim¹,

Moradi²,

Yuan³

et al. 2009

American Journal of Physiology-Renal Physiology

110

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A significant reduction of renal mass results in proteinuria, glomerulosclerosis, and tubulointerstitial injury, culminating in end-stage chronic renal failure (CRF). The accumulation of lipids in the kidney can cause renal disease. Uptake of oxidized lipoproteins via scavenger receptors, reabsorption of filtered protein-bound lipids via the megalin-cubilin complex, and increased glucose load per nephron can promote lipid accumulation in glomerular, tubular, and interstitial cells in CRF. Cellular lipid homeostasis is regulated by lipid influx, synthesis, catabolism, and efflux. We examined lipid-regulatory factors in the remnant kidney of rats 11 wk after nephrectomy (CRF) or sham operation. CRF resulted in azotemia, proteinuria, lipid accumulation in the kidney, upregulation of megalin, cubilin, mediators of lipid influx (scavenger receptor class A and lectin-like oxidized receptor-1), lipid efflux (liver X receptor α/β and ATP-binding cassette transporter), and fatty acid biosynthesis (carbohydrate-response element binding protein, fatty acid synthase, and acetyl-CoA carboxylase). However, factors involved in cholesterol biosynthesis (sterol regulatory element binding protein, 3-hydroxy-3-methylglutaryl coenzyme A reductase, SCAP, Insig-1, and Insig-2) and fatty acid oxidation (peroxisome proliferator-activated receptor, acyl-CoA oxidase, and liver-type fatty acid binding protein) were reduced in the remnant kidney. Thus CRF results in heavy lipid accumulation in the remnant kidney, which is mediated by upregulation of pathways involved in tubular reabsorption of filtered protein-bound lipids, influx of oxidized lipoproteins and synthesis of fatty acids, and downregulation of pathways involved in fatty acid catabolism.

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“…Perhaps the most consistent cytoprotective lipid yet identified is cholesterol. This conclusion is based on a series of experiments that demonstrate that diverse forms of renal injury (ischemia, toxins, oxidative stress, sepsis, heat shock, hyperosmolality; immunological injury, urinary tract obstruction) evoke increases in proximal tubular cholesterol content (19,22,(24)(25)(26)(27)(28)(29)(30). That these cholesterol increases are critical to cellular resistance to injury is indicated by a series of observations that demonstrate that 1) either reversing postinjury cholesterol increments, or preventing them (with statin or zaragozic acid therapy), cancels the cytoresistant state (11,16,22,24,29,30); and 2) alterations of cholesterol homeostasis within normal cells (e.g., via oxidation; deesterification; interference with normal P-glycoprotein-mediated cholesterol cycling) cause cellular ATP depletion and lethal cell damage (19,20).…”

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confidence: 99%

“…Based on a series of in vivo (glycerol-induced acute renal failure) and in vitro (ferrous ammonium sulfate-mediated oxidative stress) investigations from this laboratory (24,28,30), it has been hypothesized that multiple defects in cholesterol homeostasis may coexist. These include the following: 1) increased cholesterol synthesis, based on findings of increased hydroxymethylglutaryl (HMG)-CoA reductase (HMGCR) protein levels and activity (24); 2) increased LDL receptor (LDL-R) expression (28); and 3) Fe-induced reductions in ABCA1 and SR-B1 (28). The former can efflux free (i.e., unesterified) cholesterol from cells, whereas the latter may evoke bidirectional cholesterol transport (increasing cholesteryl ester uptake, FC efflux; Refs.…”

mentioning

confidence: 99%

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Proximal tubular cholesterol loading after mitochondrial, but not glycolytic, blockade

Zager

Johnson

Hanson

2003

American Journal of Physiology-Renal Physiology

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Diverse forms of injury cause proximal tubular cholesterol accumulation. However, underlying mechanisms in general, and those involved with ATP depletion injury in particular, remain poorly defined. To help elucidate this issue, cholesterol homeostasis and its determinants were assessed after partial ATP depletion states. Serum-exposed HK-2 cells were subjected to mild ATP depletion, induced by mitochondrial inhibition (antimycin A; AA) or glycolytic blockade (2-deoxyglucose; DG). Four or 18 h later, cell cholesterol levels, hydroxymethylglutaryl (HMG)-CoA reductase (HMGCR), the LDL receptor (LDL-R), and ABCA1/SR-B1 cholesterol transporters were assessed. AA and DG each induced mild, largely sublethal ATP depletion injury. Each also caused significant HMGCR increments and SR-B1 decrements and left ABCA1 intact. In contrast, only AA increased the LDL-R, and only AA evoked a cholesterol-loading state (∼25% ↑). One-half of this increase was statin inhibitable, and one-half could be blocked by serum deletion, implying that both synthetic and nonsynthetic (e.g., LDL-R transport) pathways were involved. The AA-induced HMGCR and LDL-R protein changes were paralleled by their mRNAs, suggesting the presence of altered transcriptional events. We conclude that 1) sublethal ATP depletion, whether induced by mitochondrial or glycolytic blockade, can upregulate HMGCR and decrease SR-B1, and these changes represent a previously unrecognized ATP depletion “phenotype”; 2) mitochondrial blockade can also upregulate the LDL-R and evoke a cholesterol-loading state; 3) the latter likely occurs via synthetic and transport pathways; and 4) the mitochondrion may be a critical, and previously unrecognized, determinant of postinjury cell cholesterol homeostasis, potentially by impacting the LDL-R.

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Acute Tubular Injury Causes Dysregulation of Cellular Cholesterol Transport Proteins

Abstract: 1 This is based on observations that all forms of acute renal injury tested to date (toxic, ischemic, thermal, obstructive, inflammatory) induce accumulation of free cholesterol (FC) and cholesteryl esters (CEs) within the renal cortex.

Cited by 34 publications

References 37 publications

Downregulation of liver X receptor-α in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines

Downregulation of liver X receptor-α in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines

Renal mass reduction results in accumulation of lipids and dysregulation of lipid regulatory proteins in the remnant kidney

Proximal tubular cholesterol loading after mitochondrial, but not glycolytic, blockade

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