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Kidney Week

Abstract: FR-PO190

Reduced Perivascular Cell Dynamin-Related Protein 1 (Drp1) Protects Against AKI and CKD in Mice

Session Information

  • AKI: Mechanisms - II
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Goggins, Eibhlin S., UVA Health, Charlottesville, Virginia, United States
  • Poudel, Nabin, UVA Health, Charlottesville, Virginia, United States
  • Yao, Junlan, UVA Health, Charlottesville, Virginia, United States
  • Zheng, Shuqiu, UVA Health, Charlottesville, Virginia, United States
  • Okusa, Mark D., UVA Health, Charlottesville, Virginia, United States
Background

Mitochondrial dysfunction has been implicated in the pathogenesis of AKI and CKD. We have previously demonstrated that proximal tubule deletion of Drp1 attenuated progressive kidney injury and fibrosis after ischemia-reperfusion injury (IRI). The role of Drp1 and mitochondrial dysfunction in kidney perivascular cells (PVCs) during AKI and CKD has not been explored.

Methods

PVC specific germline (Foxd1-Cre;Drp1+/-, Foxd1-Cre;Drp1-/-) or inducible (Pdgfrβ-CreERT2;Drp1+/-, Pdgfrβ-CreERT2;Drp1-/-) Drp1 heterozygote and knockout mice and respective littermate controls (WT) were generated. Foxd1-Cre;Drp1+/-, Foxd1-Cre;Drp1-/- and WT male and female mice were injected with folic acid (FA, 250 mg/kg i.p.). 24 and 48 hours later, mice were evaluated for kidney injury by plasma creatinine (PCr) and BUN and Kim-1 and Ngal mRNA. In another model of AKI, Pdgfrβ-CreERT2;Drp1+/-, Pdgfrβ-CreERT2;Drp1-/- and WT male mice underwent bilateral kidney IRI (bIRI, 26 min). In a model of the AKI to CKD progression, Foxd1-Cre;Drp1+/-, Foxd1-Cre;Drp1-/- and WT male and female mice were injected with FA and followed for 14 days. Mice were evaluated for kidney fibrosis by mRNA levels of fibrosis genes (Col1α1, Fn1) and Masson’s trichrome staining.

Results

24 hours after FA, both male and female WT mice displayed a rise in plasma creatinine and BUN which was significantly attenuated in mice with partial deletion of PVC Drp1 (Foxd1-Cre;Drp1+/-). In contrast, mice with a full deletion of Drp1 in PVCs (Foxd1-Cre;Drp1-/-) displayed an increased susceptibility to injury in male mice and increased mortality in females. 14 days after FA, Foxd1-Cre;Drp1+/- mice had reduced kidney fibrosis histologically and by mRNA levels of Col1α1 and Fn1 compared with WT and Foxd1-Cre;Drp1-/- mice. After bIRI, both Pdgfrβ-CreERT2;Drp1-/- and Pdgfrβ-CreERT2;Drp1+/- mice had a decrease in plasma creatinine compared with WT controls.

Conclusion

Reduced expression of Drp1 in PVCs had a protective effect during AKI and CKD, suggesting that PVC Drp1 could serve as a therapeutic target. Although Pdgfrβ-CreERT2;Drp1-/- mice were protected from injury, Foxd1-Cre;Drp1-/- mice displayed increased susceptibility to injury. Studies to understand the effect of timing, cellular expression and level of Drp1 reduction on AKI and CKD outcomes are ongoing.