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

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

doi:10.1152/ajprenal.00187.2003

Cited by 12 publications

(19 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Within 12 to 24 hours post-AKI induction, this culminates in an approximately 20% to 40% increase in renal cortical cholesterol content. Furthermore, when cultured human proximal tubular (HK-2) cells are subjected to either toxin or ATP depletionmediated injury, increased HMGCR activity and cholesterol accumulation result (9). The significance of these in vitro findings is that they imply that injuryinduced in vivo cholesterol accumulation reflects, at least in part, a direct proximal tubule cell event.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

HMG–CoA Reductase Activation and Urinary Pellet Cholesterol Elevations in Acute Kidney Injury

Johnson¹,

Ware²,

Himmelfarb³

et al. 2011

Clinical Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

SummaryBackground and objectives Experimental acute kidney injury (AKI) activates the HMG-CoA reductase (HMGCR) gene, producing proximal tubule cholesterol loading. AKI also causes sloughing of proximal tubular cell debris into tubular lumina. This study tested whether these two processes culminate in increased urinary pellet cholesterol content, and whether the latter has potential AKI biomarker utility.Design, setting, participants, & measurements Urine samples were collected from 29 critically ill patients with (n ϭ 14) or without (nϭ 15) AKI, 15 patients with chronic kidney disease, and 15 healthy volunteers. Centrifuged urinary pellets underwent lipid extraction, and the extracts were assayed for cholesterol content (factored by membrane phospholipid phosphate content). In vivo HMGCR activation was sought by measuring levels of RNA polymerase II (Pol II), and of a gene activating histone mark (H3K4m3) at exon 1 of the HMGCR gene (chromatin immunoprecipitation assay of urine chromatin samples).Results AKIϩ patients had an approximate doubling of urinary pellet cholesterol content compared with control urine samples (versus normal; P Ͻ 0.001). The values significantly correlated (r, 0.5; P Ͻ 0.01) with serum, but not urine, creatinine concentrations. Conversely, neither critical illness without AKI nor chronic kidney disease raised pellet cholesterol levels. Increased HMGCR activity in the AKIϩ patients was supported by three-to fourfold increased levels of Pol II, and of H3K4m3, at the HMGCR gene (versus controls or AKIϪ patients).Conclusions (1) Clinical AKI, like experimental AKI, induces HMGCR gene activation; (2) increased urinary pellet cholesterol levels result; and (3) urine pellet cholesterol levels may have potential AKI biomarker utility. The latter will require future testing in a large prospective trial.

show abstract

Section: Introductionmentioning

confidence: 99%

“…A seemingly constant consequence of ischemic or toxic acute kidney injury (AKI) is an upregulation of renal cortical HMG-CoA reductase (HMGCR) activity (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Within 12 to 24 hours post-AKI induction, this culminates in an approximately 20% to 40% increase in renal cortical cholesterol content.…”

Section: Introductionmentioning

confidence: 99%

HMG–CoA Reductase Activation and Urinary Pellet Cholesterol Elevations in Acute Kidney Injury

Johnson¹,

Ware²,

Himmelfarb³

et al. 2011

Clinical Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Clearly, increased low-density lipoprotein receptor-mediated cholesterol uptake, as well as decreased cholesterol efflux (reverse cholesterol transport) may also be involved. 14,39 However, to separate out each of these different components in vivo is extremely difficult because any single experimentally induced change in one particular cholesterol accumulation pathway (eg, statin-mediated HMGCR inhibition) can cause compensatory alteration(s) in the others (eg, a secondary increase in low-density lipoprotein receptor-mediated uptake). Hence, these types of determinations are most easily resolved in cell culture experiments in which individual pathways can be controlled.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, these types of determinations are most easily resolved in cell culture experiments in which individual pathways can be controlled. 39 The purpose of this study was to focus on the molecular determinant(s) of just one critical cholesterol homeostatic pathway: the HMGCR gene. The stimulus for this investigation was the present observation that I/R caused increases in both HMGCR protein and its cognate mRNA.…”

Section: Discussionmentioning

confidence: 99%

“…This assertion is based on observations that statin-mediated inhibition of HMG CoA reductase, the rate-limiting enzyme in cholesterol synthesis, abrogates cholesterol accumulation after injury. 31,[35][36][37][38][39] However, whether increased cholesterol synthesis reflects increased HMGCR gene transcription, and which transcription factors might stimulate this response, have not been assessed. Hence, the present study was undertaken to explore the following issues: i) Does renal ischemic preconditioning activate the HMGCR gene (as assessed by RNA polymerase II recruitment to its transcription sites)?…”

mentioning

confidence: 99%

See 1 more Smart Citation

Renal Ischemia-Induced Cholesterol Loading

Naito

Bomsztyk

Zager

2009

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

Acute kidney injury evokes renal tubular cholesterol synthesis. However, the factors during acute kidney injury that regulate HMG CoA reductase (HMGCR) activity, the rate-limiting step in cholesterol synthesis, have not been defined. To investigate these factors, mice were subjected to 30 minutes of either unilateral renal ischemia or sham surgery. After 3 days, bilateral nephrectomy was performed and cortical tissue extracts were prepared. The recruitment of RNA polymerase II (Pol II), transcription factors (SREBP-1, SREBP-2, NF-B, c-Fos, and c-Jun), and heat shock proteins (HSP-70 and heme oxygenase-1) to the HMGCR promoter and transcription region (start/ end exons) were assessed by Matrix ChIP assay. HMGCR mRNA, protein, and cholesterol levels were determined. Finally, histone modifications at HMGCR were assessed. Ischemia/reperfusion (I/R) induced marked cholesterol loading, which corresponded with elevated Pol II recruitment to HMGCR and increased expression levels of both HMGCR protein and mRNA. I/R also induced the binding of multiple transcription factors (SREBP-1, SREBP-2, c-Fos, c-Jun, NF-B) and heat shock proteins to the HMGCR promoter and transcription regions. Significant histone modifications (increased H3K4m3, H3K19Ac, and H2A.Z variant) at these loci were also observed but were not identified at either the 5 and 3 HMGCR flanking regions (؎5000 bps) or at negative control genes (␤-actin and ␤-globin). In conclusion, I/R activates the HMGCR gene via multiple stress-activated transcriptional and epigenetic pathways, contributing to renal cholesterol loading.

show abstract

Influence of Native and Hypochlorite-Modified Low-Density Lipoprotein on Gene Expression in Human Proximal Tubular Epithelium

Porubský¹,

Schmid²,

Bonrouhi³

et al. 2004

The American Journal of Pathology

View full text Add to dashboard Cite

Inflammatory infiltrates can modify (lipo)proteins via hypochlorous acid/hypochlorite (HOCl/OCl(-)) an oxidant formed by the myeloperoxidase-H(2)O(2)-halide system. These oxidatively modified proteins emerge in tubuli in some proteinuric and interstitial diseases. Human proximal tubular cells (HK-2) were used to confirm the hypothesis of detrimental and differential impact of HOCl-modified low density lipoprotein (HOCl-LDL), an in vivo occurring lipoprotein modification exerting proatherogenic and proinflammatory capacity. HOCl-LDL showed dose-dependent antiproliferative effects in HK-2 cells. Small dedicated cDNA macroarrays were used to identify differentially regulated genes. A rapid increase in the expression of genes involved in reactive oxygen species metabolism and cell stress, eg, heme oxygenase-1, thioredoxin reductase, cytochrome b5 reductase, Gadd 153, amino acid transporter E16, and HSP70 was found after HOCl-LDL treatment of HK-2 cells. In parallel, genes involved in tissue remodeling and inflammation eg, CTGF, VCAM-1, IL-1beta, MMP7, and VEGF were up-regulated. Quantitative RT-PCR verified differential expression of a subset of these genes in microdissected tubulointerstitia from patients with acute tubular damage, progressive proteinuric renal disease, and membranous glomerulonephritis (with declining renal function), but not in stable patients with proteinuria caused by minimal change disease. The demonstration of selective up-regulation of a subgroup of genes if proteinuria is accompanied by the presence of HOCl-modified (lipo)proteins support the potential pathophysiological role of the myeloperoxidase-H(2)O(2)-halide system and HOCl-LDL in renal disease.

show abstract

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

Cited by 12 publications

References 29 publications

HMG–CoA Reductase Activation and Urinary Pellet Cholesterol Elevations in Acute Kidney Injury

HMG–CoA Reductase Activation and Urinary Pellet Cholesterol Elevations in Acute Kidney Injury

Renal Ischemia-Induced Cholesterol Loading

Influence of Native and Hypochlorite-Modified Low-Density Lipoprotein on Gene Expression in Human Proximal Tubular Epithelium

Contact Info

Product

Resources

About