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Lipocalin-2 derived from adipose tissue mediates aldosterone-induced renal injury
Wai Yan Sun, … , Paul M. Vanhoutte, Yu Wang
Wai Yan Sun, … , Paul M. Vanhoutte, Yu Wang
Published September 6, 2018
Citation Information: JCI Insight. 2018;3(17):e120196. https://doi.org/10.1172/jci.insight.120196.
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Research Article Inflammation Nephrology

Lipocalin-2 derived from adipose tissue mediates aldosterone-induced renal injury

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Abstract

Lipocalin-2 is not only a sensitive biomarker, but it also contributes to the pathogenesis of renal injuries. The present study demonstrates that adipose tissue–derived lipocalin-2 plays a critical role in causing both chronic and acute renal injuries. Four-week treatment with aldosterone and high salt after uninephrectomy (ANS) significantly increased both circulating and urinary lipocalin-2, and it induced glomerular and tubular injuries in kidneys of WT mice. Despite increased renal expression of lcn2 and urinary excretion of lipocalin-2, mice with selective deletion of lcn2 alleles in adipose tissue (Adipo-LKO) are protected from ANS- or aldosterone-induced renal injuries. By contrast, selective deletion of lcn2 alleles in kidney did not prevent aldosterone- or ANS-induced renal injuries. Transplantation of fat pads from WT donors increased the sensitivity of mice with complete deletion of Lcn2 alleles (LKO) to aldosterone-induced renal injuries. Aldosterone promoted the urinary excretion of a human lipocalin-2 variant, R81E, in turn causing renal injuries in LKO mice. Chronic treatment with R81E triggered significant renal injuries in LKO, resembling those observed in WT mice following ANS challenge. Taken in conjunction, the present results demonstrate that lipocalin-2 derived from adipose tissue causes acute and chronic renal injuries, largely independent of local lcn2 expression in kidney.

Authors

Wai Yan Sun, Bo Bai, Cuiting Luo, Kangmin Yang, Dahui Li, Donghai Wu, Michel Félétou, Nicole Villeneuve, Yang Zhou, Junwei Yang, Aimin Xu, Paul M. Vanhoutte, Yu Wang

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Figure 1

WT mice treated with ANS (uninephrectomy, aldosterone 200 μg/kg/day, salt 1%) exhibited increased lipocalin-2 expressions in kidney and adipose tissues.

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WT mice treated with ANS (uninephrectomy, aldosterone 200 μg/kg/day, sal...
(A) WT and Adipo-LKO mice (12 weeks old) were subjected to sham or 4-week ANS treatment. Eplerenone (EPL) was given to the WT mice 1 week after starting the ANS treatment and continued for another 3 weeks. Serum and urine samples were collected before and after the treatment for measuring lipocalin-2 levels by ELISA. (B and C) The mRNA expression of lcn2 and the protein content of lipocalin-2 were examined in kidney and epididymal adipose tissue by qPCR (B) and ELISA (C). (D) The localization of lipocalin-2 protein in kidney and adipose tissue sections was examined by IHC using an antibody specifically recognizing murine lipocalin-2. Magnification, 400×. Scale bars: 20 μm. Data are presented as mean ± SEM; *P < 0.05 vs. WT sham controls; #P < 0.05 vs. WT ANS by ANOVA with the Bonferroni post hoc test (n = 6–8).

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