Increased proximal tubular cholesterol content: Implications for cell injury and “acquired cytoresistance”

Zager, Richard A.; Burkhart, Kristin M.; Johnson, Ali C. M.; Sacks, Benjamin

doi:10.1046/j.1523-1755.1999.00745.x

Cited by 75 publications

(129 citation statements)

References 25 publications

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“…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%

“…The "downstream" consequences of proximal tubule cholesterol loading remain incompletely defined. However, our prior work indicates that it helps mediate the phenomenon of "ischemic preconditioning" (socalled acquired cytoresistance), whereby previously injured tubular cells become resistant to further ischemic or toxic attack (1)(2)(3). Indeed, this sequence of events is analogous to the so-called heat shock response, i.e., whereby a renal stress (i.e., heat shock) upregulates cytoprotective molecules (i.e., heat shock proteins), which then confer a cytoresistant state (11,12).…”

Section: Introductionmentioning

confidence: 99%

“…Based on these promising preliminary experimental data, in the present study we sought to determine (1) whether this same phenomenon occurs in AKI patients; (2) whether evidence of increased HMGCR gene activity could be documented in patients by assessing RNA polymerase II binding (the enzyme that drives transcription) to HMGCR gene fragments in pelleted urinary chromatin samples (by chromatin immunoprecipitation, ChIP, assay [10]); and (3) whether pellet cholesterol levels might have potential utility as a clinical AKI biomarker. If positive data were to be obtained in this "proof of concept" study, they would provide a rationale for further testing in a large prospective clinical trial.…”

Section: Introductionmentioning

confidence: 99%

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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

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

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“…[1][2][3][4][5][6][7] This seems to be mediated, at least in part, by an increase in HMG CoA reductase (HMGCR)-mediated cholesterol synthesis within proximal tubule cells. 2 Given the heterogeneous nature of the above injury forms, we have postulated that tissue cholesterol accumulation can be an integral component of the renal stress response.…”

mentioning

confidence: 99%

“…Modest CE, but no FC, increases resulted, 4 differing from the aforementioned tubular injury response. [1][2][3][4][5][6][7] However, our previous NTS results were obtained at only a single early time point (48 hours), and only one disease model was studied. Hence, it remains possible that with more prolonged, or progressive, glomerular injury more dramatic renal cholesterol accumulation might result.…”

mentioning

confidence: 99%

Experimental Glomerulopathy Alters Renal Cortical Cholesterol, SR-B1, ABCA1, and HMG CoA Reductase Expression

Johnson

Yabu

Hanson

et al. 2003

The American Journal of Pathology

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Previous studies indicate that acute tubular injury causes free cholesterol (FC) and cholesteryl ester (CE) accumulation within renal cortex/proximal tubules. This study assessed whether similar changes occur with glomerulopathy/nephrotic syndrome, in which highcirculating/filtered lipoprotein levels increase renal cholesterol supply. Potential adaptive changes in cholesterol synthetic/transport proteins were also assessed. Nephrotoxic serum (NTS) or passive Heymann nephritis (PHN) was induced in Sprague-Dawley rats. Renal injury (blood urea nitrogen, proteinuria) was assessed 2 and 7 days (NTS), or 10 and 30 days (PHN) later. FC and CE levels in renal cortex, isolated glomeruli, and proximal tubule segments were determined. SR-B1 (a CE influx protein), ABCA1 (a FC exporter), and HMG CoA reductase protein/mRNA levels were also assessed. FC was minimally elevated in renal cortex (0 to 15%), the majority apparently localizing to proximal tubules. More dramatic CE elevations were found (ϳ5 to 15؋), correlating with the severity of proteinuria at any single time point (r > 0.85). Cholesterol increments were associated with decreased SR-B1, increased ABCA1, and increased HMG CoA reductase (HMGCR) protein and its mRNA. Tubule (HK-2) cell culture data indicated that SR-B1 and ABCA1 levels are responsive to cholesterol supply. Experimental nephropathy can increase renal FC, and particularly CE, levels, most notably in proximal tubules. These changes are associated with adaptations in SR-B1 and ABCA1 expression, which are physiologically appropriate changes for a cholesterol overload state. However, HMGCR protein/mRNA increments can also result. These seem to reflect a maladaptive response, potentially contributing to a cell cholesterol overload state. Previous work from this laboratory has indicated that diverse forms of renal tubular injury (eg, ischemia/reperfusion, myohemoglobinuria, sepsis syndrome, heat shock, urinary tract obstruction), can each trigger accumulation of free cholesterol (FC) and cholesteryl esters (CE) within renal cortex.

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New applications of squalene synthase inhibitors: Membrane cholesterol as a therapeutic target

Kourounakis

Bavavea

2020

Archiv der Pharmazie

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Squalene synthase (SQS) inhibitors, mostly known as antihyperlipidemic agents for controlling blood cholesterol levels, have been increasingly used to study alterations of the cholesterol content in cell membranes. As such, SQS inhibitors have been demonstrated to control cellular activities related to cancer cell proliferation and migration, neuron degeneration, and parasite growth. While the mechanisms behind the effects of cellular cholesterol are still being revealed in detail, the evidence for SQS as a therapeutic target for several seemingly unrelated diseases is increasing. SQS inhibitors may be the next promising candidates targeting the three remaining primary therapeutic areas, beyond cardiovascular disease, which still need to be addressed; their application as anticancer, antimicrobial, and antineurodegenerative agents appears promising for new drug discovery projects underway.

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Increased proximal tubular cholesterol content: Implications for cell injury and “acquired cytoresistance”

Abstract: ARF leads to an up-regulation of proximal tubule cholesterol content. The latter may then contribute to acquired CR, possibly by stabilizing the plasma membrane via its antifluidizing effect.

Cited by 75 publications

References 25 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

Experimental Glomerulopathy Alters Renal Cortical Cholesterol, SR-B1, ABCA1, and HMG CoA Reductase Expression

New applications of squalene synthase inhibitors: Membrane cholesterol as a therapeutic target

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