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

Abstract

Lipocalin-2 is not only a sensitive biomarker but 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-weeks treatment with aldosterone and high salt after uninephrectomy (ANS) significantly increased both circulating and urinary lipocalin-2, and induced glomerular and tubular injuries in kidneys of wild type (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 without lipocalin-2 (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.