Differential organ-specific inflammatory response to progranulin in high-fat diet-fed mice

Progranulin (PGRN) has been reported to bind tumor necrosis factor (TNF) receptor and to inhibit TNF alpha signaling. We evaluated the effect of augmentation of TNF alpha signaling by PGRN deficiency on the progression of kidney injury. Eight-week-old PGRN knockout (KO) and wild-type (WT) mice were fed a standard diet or high-fat diet (HFD) for 12 weeks. Albuminuria, markers of tubular damage, and renal mRNA levels of inflammatory cytokines were higher in HFD-fed KO (KO-HFD) mice than in HFD-fed WT (WT-HFD) mice. Body weight, vacuolization in proximal tubules, and systemic and adipose tissue inflammatory markers were lower in the KO-HFD mice than in the WT-HFD mice. The renal megalin expression was lower in the KO mice than in the WT mice regardless of the diet type. The megalin expression was also reduced in mouse proximal tubule epithelial cells stimulated with TNF alpha and in those with PGRN knockdown by small interfering RNA in vitro. PGRN deficiency was associated with both exacerbated renal inflammation and decreased systemic inflammation, including that in the adipose tissue of mice with HFD-induced obesity. Improved tubular vacuolization in the KO-HFD mice might partially be explained by the decreased expression of megalin in proximal tubules.

Automated summary

The study found that PGRN deficiency exacerbates inflammation in kidney injury and leads to a decrease in systemic inflammation, particularly in the adipose tissue of mice with high-fat diet-induced obesity. The reduced expression of megalin in renal tubules may partly explain the improvement in tubular vacuolization in KO-HFD mice.