The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index; 4 of the 4 sources its claims cite were checked for support.
(Pro)renin Receptor Inhibition Reduces Plasma Cholesterol and Triglycerides but Does Not Attenuate Atherosclerosis in Atherosclerotic Mice
Open accessAbstract
Objective: Elevated plasma cholesterol concentrations contributes to ischemic cardiovascular diseases. Recently, we showed that inhibiting hepatic (pro)renin receptor [(P)RR] attenuated diet-induced hypercholesterolemia and hypertriglyceridemia in low-density lipoprotein receptor (LDLR) deficient mice. The purpose of this study was to determine whether inhibiting hepatic (P)RR could attenuate atherosclerosis. Approach and Results: Eight-week-old male LDLR−/− mice were injected with either saline or N-acetylgalactosamine-modified antisense oligonucleotides (G-ASOs) primarily targeting hepatic (P)RR and were fed a western-type diet (WTD) for 16 weeks. (P)RR G-ASOs markedly reduced plasma cholesterol concentrations from 2,211 ± 146 to 1,128 ± 121 mg/dL. Fast protein liquid chromatography (FPLC) analyses revealed that cholesterol in very low-density lipoprotein (VLDL) and intermediate density lipoprotein (IDL)/LDL fraction were potently reduced by (P)RR G-ASOs. Moreover, (P)RR G-ASOs reduced plasma triglyceride concentrations by more than 80%. Strikingly, despite marked reduction in plasma lipid concentrations, atherosclerosis was not reduced but rather increased in these mice. Further testing in ApoE−/− mice confirmed that (P)RR G-ASOs reduced plasma lipid concentrations but not atherosclerosis. Transcriptomic analysis of the aortas revealed that (P)RR G-ASOs induced the expression of the genes involved in immune responses and inflammation. Further investigation revealed that (P)RR G-ASOs also inhibited (P)RR in macrophages and in enhanced inflammatory responses to exogenous stimuli. Moreover, deleting the (P)RR in macrophages resulted in accelerated atherosclerosis in WTD fed ApoE−/− mice. Conclusion: (P)RR G-ASOs reduced the plasma lipids in atherosclerotic mice due to hepatic (P)RR deficiency. However, augmented pro-inflammatory responses in macrophages due to (P)RR downregulation counteracted the beneficial effects of lowered plasma lipid concentrations on atherosclerosis. Our study demonstrated that hepatic (P)RR and macrophage (P)RR played a counteracting role in atherosclerosis.
Overview
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Written from the paper’s full text.
TL;DR
Inhibiting hepatic (P)RR with GalNAc-modified antisense oligonucleotides lowered plasma cholesterol and triglycerides in western-type diet-fed LDLR−/− and ApoE−/− mice, but did not attenuate atherosclerosis and even increased lesions in LDLR−/− mice. The counteracting effect was attributed to macrophage (P)RR downregulation promoting inflammatory cytokine production.
Key findings
- In LDLR−/− mice, (P)RR G-ASOs reduced plasma cholesterol by ~50% (2,211 ± 146 to 1,128 ± 121 mg/dL) and reduced plasma triglycerides by more than 80%, mainly in VLDL and IDL/LDL fractions.
- Despite lipid lowering, lesion sizes in the aortic arch and entire aorta were increased in LDLR−/− mice; aortic root lesions were unaltered. In ApoE−/− mice, (P)RR G-ASOs also reduced plasma cholesterol and triglycerides but did not alter lesion size in whole aorta, aortic arch, or aortic root.
- Aortic transcriptomics showed (P)RR G-ASOs upregulated 256 genes and downregulated 4 genes, with 206 genes specifically altered and enriched in immune/inflammation pathways including NF-κB, chemokine, and Toll-like receptor signaling.
- Macrophage (P)RR inhibition enhanced LPS-stimulated Tnfa, Il6, and Il1b expression and increased TNF-α, IL-6, and IL-1β secretion while reducing anti-inflammatory Il10/IL-10; macrophage-specific (P)RR knockout on ApoE−/− accelerated atherosclerosis without affecting plasma cholesterol or triglycerides.
Methods
- Eight-week-old male LDLR−/− and ApoE−/− mice were injected subcutaneously with saline or GalNAc-modified (P)RR ASOs weekly (3.0 mg/kg/week for first 4 weeks, then 1.5 mg/kg/week) and fed a western-type diet for 16 weeks; n = 8/group for LDLR−/− and n = 9/group for ApoE−/−.
- Atherosclerosis was assessed by en face Oil Red O staining of whole aorta and aortic arch, and by H&E/ORO staining of aortic root sections; plasma lipids were measured by commercial kits and FPLC, with additional blood pressure, plasma renin, and ApoB measurements.
- Aortic arch RNA sequencing used DESeq2, GO/KEGG enrichment, and GSVA; RAW264.7 macrophages were treated with (P)RR G-ASOs and LPS/nigericin; macrophage-specific (P)RR knockout ApoE−/− mice were fed WTD for 12 weeks (n = 7/group).
Limitations
- Stated: only male mice were studied, because the authors’ previous study also focused on male mice and the estrus cycle in females may affect atherosclerosis and other parameters.
- Stated in Methods: data were not tested for equal variance; comparisons used two-tailed Student t-test or one-way ANOVA with Bonferroni correction.
- Evident: changes in LDL particle size/density are inferred from increased plasma ApoB and reduced IDL/LDL cholesterol rather than directly measured, and the authors describe these as possible or likely mechanisms.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
4 of 4 cited sources checked · 1 supported · 1 flagged · accuracy not yet measured
- Premisecitation
Reduced plasma cholesterol concentrations were observed as early as 1 week after hepatic (P)RR inhibition.
“It is worthy to note that reduced plasma cholesterol concentrations were observed as early as 1 week after hepatic (P)RR inhibition (7).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [7] Ren, 2018, Circ Res. source
The Results section reports the opposite at one week: plasma cholesterol was 3- to 4-fold higher after hepatic (P)RR inhibition in high-fat-diet-fed mice, as it was in normal-diet-fed mice. The paper reports reduced cholesterol in LDLR-deficient mice after four weeks, not a reduction as early as one week. Page numbers were not available in our copy. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
- Interpretationcitation
The increased ApoB concentrations caused by hepatic (P)RR inhibition are likely a result of reduced sortilin-1 abundance.
“Since sortilin-1 promotes ApoB degradation and the (P)RR inhibition reduces sortilin-1 abundance (6, 7, 26), increased ApoB is likely a result of reduced sortilin-1 abundance.”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [6] Lu, 2016, Identification of the (Pro)renin receptor as a novel regulator of low-density lipoprotein metabolism, Circ Res. source
- cites [7] Ren, 2018, Circ Res. source
The background passage on SORT1 and ApoB (page unavailable) says SORT1 overexpression promotes ApoB degradation. The Results report that hepatic (P)RR inhibition reduces SORT1 abundance, but do not establish that reduced SORT1 causes increased ApoB concentrations; the Discussion instead links reduced SORT1 to impaired LDL clearance and describes the triglyceride effect as SORT1-independent. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [26] Strong, 2012, Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism, J Clin Invest. source
The Discussion (page not available) says sortilin promotes lysosomal degradation of APOB and reports that disrupting liver sortilin expression can increase APOB/VLDL secretion. This supports the proposed mechanism, but the paper does not examine (P)RR inhibition or establish that it reduces sortilin abundance and thereby raises APOB. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Findingown data
In ApoE−/− mice fed a western-type diet, (P)RR G-ASOs reduced plasma cholesterol and triglyceride concentrations to a similar extent as in LDLR−/− mice.
“We found that (P)RR G-ASOs also effectively reduced both plasma cholesterol and triglyceride concentrations in ApoE−/− mice (Figures 2A,B; Supplementary Figure II), into a similar extent as observed in LDLR−/− mice.”
Quote in the paperSubstantial claim - Findingown data
In the aortic arch region, 206 genes were specifically altered by (P)RR G-ASOs.
“We then compared the DEGs and found that 206 genes were specifically altered by (P)RR G-ASOs (Supplementary Table V; Figure 3B).”
Quote in the paperSubstantial claim - Findingown data
In LDLR−/− mice, (P)RR G-ASOs potently reduced cholesterol in the VLDL and IDL/LDL fractions.
“FPLC analysis revealed that the cholesterol contents of VLDL and IDL/LDL fractions were the most reduced (Figure 1A).”
Quote in the paperSubstantial claim
- Findingown data
IDL/LDL cholesterol was reduced by about 30% by inhibiting hepatic (P)RR.
“Moreover, IDL/LDL cholesterol, the most potent atherogenic cholesterol, was reduced by ~30% by inhibiting hepatic (P)RR inhibition.”
Quote in the paperSubstantial claim - Findingown data
In LDLR−/− mice fed a western-type diet, (P)RR G-ASOs increased lesion sizes in the aortic arch region and the entire aorta.
“Strikingly, lesion sizes in the aortic arch region and the entire aorta were increased rather than reduced by (P)RR inhibition (Figures 1C–E).”
- Also stated in: § Abstract · plain
“Strikingly, despite marked reduction in plasma lipid concentrations, atherosclerosis was not reduced but rather increased in these mice.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingreasoning
(P)RR G-ASOs did not attenuate atherosclerosis in WTD-fed LDLR−/− and ApoE−/− mice.
“Overall, (P)RR G-ASOs did not attenuate atherosclerosis in WTD-fed LDLR−/− and ApoE−/− mice.”
Quote in the paperSubstantial claim - Findingown data
(P)RR G-ASOs inhibited (P)RR expression in macrophages, including peritoneal macrophages from C57BL/6J mice and RAW264.7 cells.
“Indeed, isolated peritoneal macrophages from C57BL/6J mice administered (P)RR G-ASO for 1 week have showed marked reduction in (P)RR expression (Supplementary Figure VIA).”
- Also stated in: § (P)RR G-ASOs Promoted Immune Responses by Stimulating Macrophage Inflammatory Cytokines · plain
“Moreover, a successfully inhibited (P)RR expression in murine RAW264.7 (Supplementary Figure VIB), a widely used murine macrophage cell line, has enhanced LPS-stimulated expression of pro-inflammatory cytokines, including Tnfa, Il6 and Il1b (Figure 3E).”
Quote in the paperSubstantial claim - Also stated in: § (P)RR G-ASOs Promoted Immune Responses by Stimulating Macrophage Inflammatory Cytokines · plain
- Findingown data
In LDLR−/− mice, (P)RR G-ASOs did not alter lesion sizes in the aortic root.
“However, lesions sizes in the aortic root, revealed by H&E and ORO staining, were unaltered by (P)RR inhibition (Figure 1F).”
Quote in the paperSubstantial claim - Findingown data
Deleting (P)RR in macrophages did not affect plasma cholesterol and triglyceride concentrations in ApoE−/− mice.
“We found that deleting the (P)RR in macrophages did not affect plasma cholesterol and triglyceride concentrations (Figures 4A,B), further confirming that lowered plasma lipid concentrations were due to hepatic (P)RR deficiency.”
Quote in the paperSubstantial claim - Findingown data
Plasma ApoB concentrations were increased by inhibiting hepatic (P)RR.
“Indeed, we found that plasma ApoB concentrations were increased by inhibiting hepatic (P)RR (Supplementary Figure IX).”
Quote in the paperSubstantial claim - Findingown data
Macrophage (P)RR-deleted ApoE−/− mice showed accelerated atherosclerosis development.
“But, macrophage (P)RR-deleted mice did show accelerated atherosclerosis development (Figures 4C–F).”
Quote in the paperSubstantial claim - Interpretationown data
The lowered plasma lipid concentrations produced by (P)RR G-ASOs in atherosclerotic mice are due to hepatic (P)RR deficiency.
“(P)RR G-ASOs reduced the plasma lipids in atherosclerotic mice due to hepatic (P)RR deficiency.”
- Also stated in: § (P)RR G-ASOs Promoted Immune Responses by Stimulating Macrophage Inflammatory Cytokines · boosted
“further confirming that lowered plasma lipid concentrations were due to hepatic (P)RR deficiency.”
- Also stated in: § Discussion · boosted
“In summary, we showed that (P)RR G-ASOs lowered the plasma lipid concentrations in WTD-fed LDLR−/− and ApoE−/− mice due to hepatocyte (P)RR inhibition.”
Quote in the paperSubstantial claim - Also stated in: § (P)RR G-ASOs Promoted Immune Responses by Stimulating Macrophage Inflammatory Cytokines · boosted
- Interpretationreasoning
The densities of LDL particles were likely increased by hepatic (P)RR inhibition.
“This finding, together with reduced cholesterol content in the IDL/LDL fraction, suggested that the densities of LDL particles were likely increased by hepatic (P)RR inhibition.”
Quote in the paperSubstantial claim - Interpretationown data
Augmented pro-inflammatory responses in macrophages due to (P)RR downregulation counteracted the beneficial effects of lowered plasma lipid concentrations on atherosclerosis.
“However, augmented pro-inflammatory responses in macrophages due to (P)RR downregulation counteracted the beneficial effects of lowered plasma lipid concentrations on atherosclerosis.”
Quote in the paperSubstantial claim - Interpretationreasoning
Hepatic (P)RR and macrophage (P)RR played counteracting roles in atherosclerosis.
“Our study demonstrated that hepatic (P)RR and macrophage (P)RR played a counteracting role in atherosclerosis.”
Quote in the paperSubstantial claim - Interpretationown data
(P)RR G-ASOs promote immune responses in the aorta by augmenting macrophage inflammatory cytokine production.
“Transcriptomic analysis of the aortas revealed that (P)RR G-ASOs induced the expression of the genes involved in immune responses and inflammation. Further investigation revealed that (P)RR G-ASOs also inhibited (P)RR in macrophages and in enhanced inflammatory responses to exogenous stimuli.”
- Also stated in: § (P)RR G-ASOs Promoted Immune Responses by Stimulating Macrophage Inflammatory Cytokines · hedged
“Collectively, these findings suggested that suppressed (P)RR expression in macrophages has enhanced inflammatory responses in lesions, counteracting the benefits of lowered plasma lipid concentrations by hepatic (P)RR inhibition.”
Quote in the paperSubstantial claim - Also stated in: § (P)RR G-ASOs Promoted Immune Responses by Stimulating Macrophage Inflammatory Cytokines · hedged
- It may state two separate claims as one. 8
- The quote only partly states this claim. 2
It may state two separate claims as one.
Findingown dataIn RAW264.7 cells, (P)RR inhibition increased TNF-α, IL-6, and IL-1β secretion and decreased IL-10 secretion.
“In line with the gene expression findings, (P)RR inhibition in RAW264.7 increased TNF-α, IL-6 and IL-1β secretion, and decreased IL-10 secretion (Figure 3F; Supplemental Figure VII).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn the aortic arch region of LDLR−/− mice fed a western-type diet for 4 weeks, (P)RR G-ASOs upregulated 256 genes and downregulated 4 genes, enriched in immune-response-related biological processes.
“In comparison, (P)RR G-ASOs upregulated 256 genes and downregulated 4 genes, which are also enriched in immune- response-related biological processes (Supplementary Table IV; Supplementary Figure IV).”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataIn 8-week-old male LDLR−/− mice fed a western-type diet for 16 weeks, (P)RR G-ASOs reduced plasma cholesterol concentrations from 2,211 ± 146 to 1,128 ± 121 mg/dL, a reduction of about 50%.
“(P)RR G-ASOs markedly reduced plasma cholesterol concentrations from 2,211 ± 146 to 1,128 ± 121 mg/dL.”
- Also stated in: § (P)RR G-ASOs Did Not Ameliorate but Increased Atherosclerosis in LDLR–/– Mice · plain
“Inhibiting the (P)RR in hepatocytes reduced the plasma cholesterol concentrations by ~50% (2,211 ± 146 vs. 1128 ± 121 mg/dL)”
Quote in the paperSubstantial claim- Also stated in: § (P)RR G-ASOs Did Not Ameliorate but Increased Atherosclerosis in LDLR–/– Mice · plain
It may state two separate claims as one.
Findingown dataIn the aortic arch region of (P)RR G-ASO-administered LDLR−/− mice, GSVA showed activation of an inflammatory gene set, the type I interferon response gene set, and the M1 macrophage signature gene set.
“GSVA analysis demonstrated that inflammatory gene set, which is type I interferon response gene set, and M1 macrophage signature gene set were activated (Figure 3D), suggesting enhanced inflammation in the aortic arch region of (P)RR G-ASOs administered LDLR−/− mice.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataInhibiting (P)RR in RAW264.7 macrophages enhanced LPS-stimulated expression of pro-inflammatory cytokines Tnfa, Il6, and Il1b, and reduced Il10 expression with or without LPS stimulation.
“Moreover, a successfully inhibited (P)RR expression in murine RAW264.7 (Supplementary Figure VIB), a widely used murine macrophage cell line, has enhanced LPS-stimulated expression of pro-inflammatory cytokines, including Tnfa, Il6 and Il1b (Figure 3E). In RAW264.7 cells, inhibiting the (P)RR has reduced the abundance of Il10, which is an anti-inflammatory cytokine, done either with or without LPS”
Quote in the paperSubstantial claimIt may state two separate claims as one. The quote only partly states this claim.
Findingown dataIn LDLR−/− mice, (P)RR G-ASOs reduced plasma triglyceride concentrations by more than 80%, mainly by reducing VLDL and IDL/LDL triglycerides.
“Moreover, (P)RR G-ASOs reduced plasma triglyceride concentrations by more than 80%.”
- Also stated in: § (P)RR G-ASOs Did Not Ameliorate but Increased Atherosclerosis in LDLR–/– Mice · plain
“Plasma triglyceride concentrations were also significantly reduced, mainly by reducing VLDL and IDL/LDL-triglycerides (Figure 1B).”
Quote in the paperSubstantial claim- Also stated in: § (P)RR G-ASOs Did Not Ameliorate but Increased Atherosclerosis in LDLR–/– Mice · plain
It may state two separate claims as one.
Findingown dataIn ApoE−/− mice, (P)RR G-ASOs did not alter lesion size in the whole aorta, aortic arch region, or aortic root.
“However, despite the marked reduction in plasma lipids concentrations, lesion size in the whole aorta and aortic arch region has remained unaltered by (P)RR inhibition (Figures 2C–E). Moreover, lesion sizes of the aortic root, revealed by H&E and ORO staining, were also unaltered by (P)RR G-ASOs (Figure 2F).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataGenes specifically altered by (P)RR G-ASOs in the aortic arch were related to immune responses, and inflammation-related pathways such as NF-κB, chemokine, and Toll-like receptor signaling were mostly affected.
“GO enrichment analysis revealed that these genes were related to immune responses (Supplementary Figure V), while KEGG enrichment analysis revealed that inflammation related pathways, such as NF-κB signaling pathway, chemokine signaling pathway, and Toll-like receptor signaling pathway, were mostly affected (Figure 3C).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
InterpretationreasoningLDLR and ApoE were not required for the lipid-lowering effects of (P)RR inhibition.
“Since plasma lipid-lowering effects were observed in both LDLR−/− and ApoE−/− mice, while (P)RR inhibition reduces hepatic LDLR abundance, the results therefore indicate that LDLR and ApoE were not required for the lipid-lowering effects of (P)RR inhibition.”
Quote in the paperSubstantial claim
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Ye, C., Jiang, W., Hu, T., Liang, J., & Chen, Y. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25147897 · Cited by 6
Soluble (pro)renin receptor as a novel laboratory biomarker of atherosclerosis
Liu, C., Song, S., Yi, X., Yang, H., Xiong, J., Wang, M., Tan, W., Zhu, M., Zheng, L., Yu, J., et al. (2024) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2024150 · Cited by 6
Kim, H. K., & Han, J. (2026) · Korean Circulation Journal · doi:10.4070/kcj.2026.0332
Metadata
- Authors
- Ye, D., Yang, X., Ren, L., Lu, H. S., Sun, Y., Lin, H., Tan, L., Wang, N., Nguyen, G., Bader, M., Mullick, A. E., Danser, A. H. J., Daugherty, A., Jiang, Y., Sun, Y., Li, F., & Lu, X.
- Affiliations
- University of Kentucky (US)
- Jinan University (CN)
- Erasmus MC (NL)
- Shenzhen University (CN)
- Ionis Pharmaceuticals (United States) (US)
- Corresponding author
- Li, Furong
- Lu, Xifeng
- ORCID
- Venue
- Frontiers in Cardiovascular Medicine
- Publisher
- Frontiers Media SA
- Published
- 2021-12-24
- Volume
- 8
- Pages
- 725203-725203
- ISSN
- 2297-055X (ISSN-L)
- PMC
- PMC8739895
- OpenAlex
- W4200004801
- Cited by
- 6
- References
- 35
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4
- FWCI
- 0.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Cardiovascular Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (JCYJ20190808170401660, 81800383, JCYJ20180305124812444, 81870605, 81670702, ZDSYS20190902092903237)
- Top Institute Pharma (T2-301)
- Basic and Applied Basic Research Foundation of Guangdong Province
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- prorenin receptor, renin-angiotensin system, atherosclerosis, hypercholesterolemia, hypertriglyceridemia, antisense oligonucleotides, Ldlr-deficient mice, ApoE-deficient mice, serum cholesterol, plasma triglycerides, inflammation, macrophage inflammation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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