The proinflammatory adipokine lipocalin-2 is upregulated in obese individuals and is thought to drive renal injuries; however, the source of lipocalin-2 during kidney dysfunction is not fully understood. In this episode, Wai Yan Sun, Bo Bai, and colleagues used multiple murine models of chronic and acute kidney injury to evaluate the role of lipocalin-2. Adipose-tissue-specific deletion, but not whole-body or kidney-specific deletion, of lipocalin-2 protected mice from aldosterone- and high salt after uninephrectomy-induced kidney damage. Moreover, transplantation of WT fat pads into animals with lipocalin-2 deficient adipose tissue restored sensitivity to renal damage, and mice chronically exposed to a stable variant of human lipocalin-2 developed renal injury. Together, these results identify adipose-generated lipocalin-2 as a driver of acute and chronic kidney dysfunction.
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.
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