Lipocalin-2 derived from adipose tissue mediates aldosterone-induced renal injury
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
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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Research Article Inflammation Nephrology

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

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 5

Lipocalin-2 of nonkidney source mediated aldosterone-induced acute renal injuries.

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Lipocalin-2 of nonkidney source mediated aldosterone-induced acute renal...
(A) Wt1CreERT2-LKO mice were treated with vehicle or tamoxifen (33 mg/kg/day, i.p. injection for 5 days). After treatment, lcn2 expressions in kidney and epididymal adipose tissue were examined by qPCR and presented as fold changes against WT controls. (B) The 24-hour urine and serum samples were collected to measure lipocalin-2 levels by ELISA. (C ) WT, Adipo-LKO, and Wt1CreGFP-LKO mice were injected with 1 dose of either vehicle or aldosterone (2 mg/kg; s.c.) as described in the Methods. The 24-hour urine samples were collected to compare urination (C, left). qPCR and ELISA were performed to measure the mRNA expressions of lcn2 and protein amounts of lipocalin-2 in kidney (C, middle and right). (D) Renal injury markers, including clu, kim-1, and wt1 were examined by qPCR and presented as fold changes against the WT vehicle controls. Data are shown as mean ± SEM; *P < 0.05 vs. WT vehicle groups; ‡P < 0.05 vs. Wt1CreERT2-LKO with vehicle treatment; #P < 0.05 vs. WT treated with aldosterone by Mann-Whitney nonparametric Student’s t test (n = 6).