Kidney Week

Abstract: SA-PO323

Podocyte-Specific Deletion of Hypoxia-Inducible Factor 1α (Hif-1α) Identifies Downstream Mediators That Are Targets to Prevent Proteinuria and Subsequent Glomerulosclerosis

Session Information

• Cellular Crosstalk in Glomerular Diseases - II
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

• Liang, Xiaoyan, Northwestern University, Chicago, Illinois, United States

Xiaoyan Liang,

• Schnaper, H. William, Northwestern University, Chicago, Illinois, United States

H. William Schnaper,

• Hayashida, Tomoko, Northwestern University, Chicago, Illinois, United States

Tomoko Hayashida,

Background

While augmentation of signals mediated by HIFs preserves organs in ischemia, the role of HIFs in more chronic glomerulopathies following podocyte injury is rather controversial. We recently reported that mice in which systemic knockout of HIF-1α is induced at the age of 6 weeks demonstrate significantly less fibrosis in Adriamycin (ADR)-induced glomerulopathy. Others previously reported that podocyte-specific deletion of von Hippel Lindau protein, that targets HIFs for degradation, resulted in increased expression of HIFs and severe glomerulopathy in mice. These results suggest that HIFs aggravate glomerular injury. Here, we further evaluated the roles of HIF specifically in podocytes, using mice that lack podocyte HIF-1α.

Methods

HIF-1α^f/f mice were crossed with NPHS2-Cre mice. Adriamycin (ADR, 10mg/kgBW) was administered intravenously to the HIF-1α ^-/-Podo or their wild-type (WT) littermates to induce glomerulopathy, and urine and kidneys were obtained on day14. RNA was isolated from cryosectioned glomerular samples using laser-capture microdissection, and HIF-1α-target gene were evaluated by qPCR. HIF-1α knockdown podocytes were generated using lenti-viral shRNAs.

Results

HIF-1α^-/-Podo mice were viable and no proteinuria was detected basally. ADR caused severe proteinuria, glomerular fibrosis and podocyte effacement in WT mice, whereas in HIF-1α^-/-Podo mice, proteinuria and glomerular sclerosis were minimally observed and podocyte structures were preserved. Among known HIF-1α-target genes tested, Irg2 and Mif were increased in glomeruli of WT mice treated with ADR but not in HIF-1α^-/-Podo mice, whereas ApoE expression was elevated in both WT and HIF-1α^-/-Podo glomeruli. PGK expression was not changed in either group of mice. In cultured mouse podocytes, Mix1, Eef1a1 and ApoE were differentially expressed in the presence or absence of HIF-1α after TGF-β1 treatment, whereas Irf7, Mt2 and Plod2 were regulated independent of HIF-1α.

Conclusion

We have identified several HIF-1α target genes that could play a role in in proteinuria and glomerulosclerosis. These could be novel therapeutic targets for glomerulopathy.

Funding

• NIDDK Support