Kidney Week

Abstract: SA-PO777

Pericyte-Specific Manipulation of Hypoxia-Inducible Factors Regulates Erythropoiesis Without Aggravating Renal Fibrosis

Session Information

• CKD: Mechanisms - III
  November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2103 CKD (Non-Dialysis): Mechanisms

Authors

• Pan, Szu-Yu, Far Eastern Memorial Hospital, New Taipei City, Taiwan

Szu-Yu Pan,

• Tsai, Pei-Zhen, National Taiwan University College of Medicine, Taipei, Taiwan

Pei-Zhen Tsai,

• Chu, Tzong-Shinn, National Taiwan University Hospital, Taipei, Taiwan

Tzong-Shinn Chu,

• Lin, Shuei-Liong, National Taiwan University Hospital, Taipei, Taiwan

Shuei-Liong Lin,

Background

Stabilizers of hypoxia-inducible factor (HIF) have been shown to be effective on treatment of anemia in patients with chronic kidney disease (CKD). Increased erythropoietin (EPO) production and enhanced erythropoiesis are known to be the major mechanisms responsible for the treatment effects. However, the effect of HIF stabilization on renal fibrosis is controversial. We created animal models characterized by CKD and pericyte-specific or non-selective stabilization of HIF to examine the effects of HIF on renal fibrosis and erythropoiesis.

Methods

Gli1^CreERT2/+;Egln1^F/F, Gli1^CreERT2/+;Vhl^F/F, and Gli1^CreERT2/+;Hif1a^F/F;Hif2a^F/F mice were generated to study the effects of pericyte-specific overexpression or knockout of Hif. Tg(UBC-CreERT2);Egln1^F/F, Tg(UBC-CreERT2);Vhl^F/F, and Tg(UBC-CreERT2);Vhl^F/F;Hif1a^F/F;Hif2a^F/F mice were generated to study the effects of non-selective stabilization of HIF. Unilateral ureteral obstruction (UUO) was used to induce CKD. The severity of fibrosis was determined by Picrosirius red stain and Col1a1 mRNA level in the kidney.

Results

Pericyte-specific stabilization of HIF resulted in increased serum EPO level, augmented splenic erythropoiesis, and polycythemia, while the severity of renal fibrosis was not affected. In line with these findings, pericyte-specific knockout of Hif1a or Hif2a did not result in significant change of renal fibrosis. We further examined the role of HIF stabilization in mice with postnatal global stabilization of HIF. Surprisingly, unexpected mortality developed along with dramatically increased serum EPO levels in a HIF-dependent manner.

Conclusion

Our study endorses the neutral effects of pericyte-specific HIF stabilization on renal fibrosis. However, the possible risks of artificially increased serum EPO level warrant further study.

Funding

• Government Support - Non-U.S.