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Abstract: FR-PO1008

Proximal Tubular FHL2 Mediates Obesity-Induced Renal Tubulointerstitial Inflammation via Regulating FoxO1 Activity

Session Information

Category: CKD (Non-Dialysis)

  • 2303 CKD (Non-Dialysis): Mechanisms

Authors

  • Wang, Yan, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  • He, Weichun, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
Background

Lipid accumulation caused by fatty acid β-oxidation deficiency in renal proximal tubular cells (PTCs) is a major factor triggering obesity-related chronic kidney disease (OR-CKD), and the low activity of forkhead box class O1 (FoxO1) is a key mediator between metabolic abnormalities and cellular damage. It was reported that four and a half LIM domain-only protein 2 (FHL2) could inhibit FoxO1 activity in prostate cancer cells. However, the potential effect of FHL2 on FoxO1 activity and lipid toxicity injury in PTCs during OR-CKD remains to be elucidated.

Methods

Mice with PTCs-specific deletion of FHL2 were generated by mating FHL2-floxed mice with Ggt1-Cre transgenic mice. The expression and function of FHL2 were examined in palmitate acid (PA)-stimulated NRK-52E cells (rat PTCs) and in the kidneys from mice with obesity induced by high-fat diet, respectively.

Results

PA induced FHL2 expression in a time- or dose-dependent manner in cultured NRK-52E cells. Knockdown of FHL2 via small interfering RNA largely suppressed PA-induced mRNA expression of several inflammatory factors including interleukin-6, monocyte chemoattractant protein-1, and tumor necrosis factor α (TNFα). In vivo, FHL2 was induced in renal PTCs in the obesity mice at 16 weeks after feeding on high-fat diet. Compared with wild-type littermates, the kidneys from mice with PTCs-specific ablation of FHL2 exhibited less interstitial inflammation, lower levels of urinary neutropil gelatinase-associated lipocalin, and lower urinary albumin-creatinine ratio. In vitro, PA induced FHL2 physically interact with FoxO1 in the nuclei. Treatment with PA resulted in a decrease in FoxO1 activity, which was evidenced by an increase in the phosphorylation (Ser256) of FoxO1 and a decrease in the abundance of FoxO1 in the nuclei. Knockdown of FHL2 inhibited the phosphorylation (Ser256) of FoxO1 in cells treated with PA, whereas ectopic expression of FHL2 promoted the phosphorylation (Ser256) of FoxO1. In addition, ChIP assay revealed that TNFα-induced protein 1 (TNFAIP1), an inhibitor of NF-κB signaling, was a putative downstream target gene of FoxO1.

Conclusion

Our results suggest that FHL2, via regulating FoxO1 activity, plays a crucial role in mediating PA-induced inflammatory reaction in PTCs and contributes to tubulointerstitial inflammation and kidney damage resulted from obesity.

Funding

  • Government Support – Non-U.S.