Clusterin/Apolipoprotein J Attenuates Angiotensin II-Induced Renal Fibrosis

Jung, Gwon-Soo; Jeon, Jae‐Han; Jung, Yuna; Choi, Youn‐Hee; Kim, Hye-Soon; Kim, Jung‐Guk; Park, Keun-Gyu; Kim, Mi-Kyung; Lee, Inkyu

doi:10.1371/journal.pone.0105635

Cited by 16 publications

(14 citation statements)

References 43 publications

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“…Therefore, our present results suggest the possible role of clusterin in renal function although eGFR was only mildly decreased. In support of our results, previous studies have shown the protective role of clusterin in Ang II‐induced renal fibrosis, ischemia‐reperfusion renal injury, chronic glomerular kidney disease of aging, and obesity‐induced kidney damage . Additionally, subgroup analysis in our studies showed that participants in the highest clusterin tertile had an increased OR for PCAD, especially in people with eGFR<90 mL/min/1.73 m 2 and Urea<7.14 mmol/L.…”

Section: Discussionsupporting

confidence: 92%

High serum clusterin levels are associated with premature coronary artery disease in a Chinese population

Zhu

Liu

Zhai

et al. 2019

Diabetes Metabolism Res

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Background: Clusterin plays an important role in the cardiovascular system, and serum levels of clusterin are higher in coronary artery disease patients. Here, we measured serum clusterin levels in premature coronary artery disease (PCAD) patients and explored the association of these levels with PCAD risk. Methods:Serum samples and general clinical information were obtained from 672 subjects including 364 PCAD subjects, 126 non-PCAD subjects, and 182 controls.Results: Serum clusterin levels were higher in PCAD patients than in controls, particularly in males with body mass index (BMI) < 25 kg/m 2 (P < 0.0001). Compared with the lowest tertile of clusterin, the odds ratio of PCAD in the highest tertile was higher in both a univariate and three adjustment models, and it was 3.146-fold higher in Model 3. This association was especially significant in subgroups with BMI < 25 kg/m 2 , total cholesterol < 5.7 mmol/L, high-density lipoprotein cholesterol ≥ 1.0 mmol/L, Urea < 7.14 mmol/L, and estimated glomerular filtration rate < 90 mL/min/1.73 m 2 . Serum clusterin may be a potential diagnostic biomarker for PCAD (sensitivity 60.7%, specificity 51.6%, area under the curve 0.595 [95% CI, 0.544-0.647], P < 0.0001), and a combination of clusterin with clinical variables in Model 3 resulted in improved diagnostic accuracy (sensitivity 86.3%, specificity 64.2%, area under the curve 0.829 [95% CI, 0.782-0.877], P < 0.0001).Conclusions: Serum clusterin levels were increased in PCAD patients, especially for males with BMI < 25 kg/m 2 . Higher clusterin levels were independently associated with the presence of PCAD, particularly in subjects with normal BMI, lower total cholesterol, urea, estimated glomerular filtration rate, and higher high-density lipoprotein cholesterol. Clusterin might be a potential diagnostic biomarker for PCAD patients, especially in combination with clinical variables. KEYWORDS body mass index (BMI), clusterin, nonpremature coronary artery disease (NPCAD), premature coronary artery disease (PCAD), risk factors

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Section: Discussionsupporting

confidence: 92%

High serum clusterin levels are associated with premature coronary artery disease in a Chinese population

Zhu

Liu

Zhai

et al. 2019

Diabetes Metabolism Res

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“…Improved clearance was associated with decreased levels of fibronectin, a heparan sulphate proteoglycan that has been shown to accelerate the aggregation of Aβ in vitro and contribute to the development of CAA in vivo . Although more work is needed to determine how clusterin contributes to clearance of Aβ via IPAD pathways, clusterin has been shown to contribute to the production and maintenance of the basement membrane and regulates the differentiation of vascular smooth muscle cells , which contribute to the motive force that drives IPAD .…”

Section: Discussionmentioning

confidence: 99%

Knockout of apolipoprotein A‐I decreases parenchymal and vascular β‐amyloid pathology in the Tg2576 mouse model of Alzheimer's disease

Contu

Carare

Hawkes

2019

Neuropathology Appl Neurobio

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Aims Apolipoprotein A‐I (apoA‐I), the principal apolipoprotein associated with high‐density lipoproteins in the periphery, is also found at high concentrations in the cerebrospinal fluid. Previous studies have reported either no impact or vascular‐specific effects of apoA‐I knockout (KO) on β‐amyloid (Aβ) pathology. However, the putative mechanism(s) by which apoA‐I may influence Aβ deposition is unknown. Methods We evaluated the effect of apoA‐I deletion on Aβ pathology, Aβ production and clearance from the brain in the Tg2576 mouse model of Alzheimer's disease (AD). Results Contrary to previous reports, deletion of the APOA1 gene significantly reduced concentrations of insoluble Aβ40 and Aβ42 and reduced plaque load in both the parenchyma and blood vessels of apoA‐I KO × Tg2576 mice compared to Tg2576 animals. This was not due to decreased Aβ production or alterations in Aβ species. Levels of soluble clusterin/apoJ were significantly higher in neurons of apoA‐I KO mice compared to both wildtype (WT) and apoA‐I KO × Tg2576 mice. In addition, clearance of Aβ along intramural periarterial drainage pathways was significantly higher in apoA‐I KO mice compared to WT animals. Conclusion These data suggest that deletion of apoA‐I is associated with increased clearance of Aβ and reduced parenchymal and vascular Aβ pathology in the Tg2576 model. These results suggest that peripheral dyslipidaemia can modulate the expression of apolipoproteins in the brain and may influence Aβ clearance and aggregation in AD.

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“…However, the biological importance of CLU for the kidney is not fully understood. We and others have been investigating the biological impacts of CLU deficiency on adult kidneys using CLU knockout (KO) mice compared to CLU-expressing wild type (WT) control mice, and have demonstrated: (i) CLU KO in aging mice results in developing progressive glomerulopathy that is associated with glomerular antibody deposition [ 30 ]; (ii) CLU KO mice exhibit the higher levels of renal fibrosis in response to ureteral obstruction [ 31 ] or angiotensin II stimulation [ 32 ]; and (iii) our group has shown that CLU KO results in more severe renal IRI [ 26 ], in an experimental model of ischemic AKI, and also impairs renal repair after IRI [ 33 ]. However, the role of CLU in the progression to CKD from AKI has not been investigated yet.…”

Section: Introductionmentioning

confidence: 99%

Relationship of clusterin with renal inflammation and fibrosis after the recovery phase of ischemia-reperfusion injury

et al. 2016

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BackgroundLong-term outcomes after acute kidney injury (AKI) include incremental loss of function and progression towards chronic kidney disease (CKD); however, the pathogenesis of AKI to CKD remains largely unknown. Clusterin (CLU) is a chaperone-like protein that reduces ischemia-reperfusion injury (IRI) and enhances tissue repair after IRI in the kidney. This study investigated the role of CLU in the transition of IRI to renal fibrosis.MethodsIRI was induced in the left kidneys of wild type (WT) C57BL/6J (B6) versus CLU knockout (KO) B6 mice by clamping the renal pedicles for 28 min at the body temperature of 32 °C. Tissue damage was examined by histology, infiltrate phenotypes by flow cytometry analysis, and fibrosis-related gene expression by PCR array.ResultsReduction of kidney weight was induced by IRI, but was not affected by CLU KO. Both WT and KO kidneys had similar function with minimal cellular infiltration and fibrosis at day 14 of reperfusion. After 30 days, KO kidneys had greater loss in function than WT, indicated by the higher levels of both serum creatinine and BUN in KO mice, and exhibited more cellular infiltration (CD8 cells and macrophages), more tubular damage and more severe tissue fibrosis (glomerulopathy, interstitial fibrosis and vascular fibrosis). PCR array showed the association of CLU deficiency with up-regulation of CCL12, Col3a1, MMP9 and TIMP1 and down-regulation of EGF in these kidneys.ConclusionOur data suggest that CLU deficiency worsens renal inflammation and tissue fibrosis after IRI in the kidney, which may be mediated through multiple pathways.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-016-0348-x) contains supplementary material, which is available to authorized users.

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Clusterin/Apolipoprotein J Attenuates Angiotensin II-Induced Renal Fibrosis

Cited by 16 publications

References 43 publications

High serum clusterin levels are associated with premature coronary artery disease in a Chinese population

High serum clusterin levels are associated with premature coronary artery disease in a Chinese population

Knockout of apolipoprotein A‐I decreases parenchymal and vascular β‐amyloid pathology in the Tg2576 mouse model of Alzheimer's disease

Relationship of clusterin with renal inflammation and fibrosis after the recovery phase of ischemia-reperfusion injury

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