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Kidney Week

Abstract: SA-PO086

Deletion of Spns2 in Proximal Tubules Protects the Mouse Kidney During Ischemia-Reperfusion Injury

Session Information

  • AKI: Mechanisms - III
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Cechova, Sylvia, University of Virginia, Charlottesville, Virginia, United States
  • Yao, Junlan, University of Virginia, Charlottesville, Virginia, United States
  • Poudel, Nabin, University of Virginia, Charlottesville, Virginia, United States
  • Okusa, Mark D., University of Virginia, Charlottesville, Virginia, United States

Group or Team Name

  • Division of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine
Background

Spns2 (Spinster homolog 2) is a non-ATP dependent organic ion transporter of S1P (Sphingosine 1-phosphate) that transports S1P from the intracellular to the extracellular cell compartment. Since 2009, several studies demonstrated the important role of SPNS2 in lymphocyte trafficking, immune responses, vascular and embryonic development, many type of cancers, and human liver fibrosis. Previously we demonstrated that Spns2 is expressed in proximal tubules and podocytes. In the present study, we investigated the effect of Spns2 deletion in mice renal proximal tubules (PTs) after bilateral ischemia-reperfusion injury (bi-IRI).

Methods

Tamoxifen inducible proximal tubule tissue specific transgenic SLC34a1-GFPCreERT2/Spns2fl/fl mice (PT-KO mice) where injected with 1mg of tamoxifen for 5 days and rested for 2 weeks before they underwent bi-IRI (28 min). 24 hours later, we collected plasma and kidney tissues. The relative mRNA expression of Spns2, Ngal, Kim1 and chemokines Cxcl1 and Cxcl10 in kidneys were estimated by qPCR. To detect protein level of Spns2 we performed gel electrophoresis and Western blot analyses of kidney tissue lysates. To evaluate kidney injuries we measured plasma creatinine, BUN, and calculated ATN score of H&E stained kidney sections.

Results

After IRI, we observed significantly decreased mRNA expression of Spns2, Ngal, Kim1, and chemokines Cxcl1 and Cxcl10 in the kidney lysates of PT-KO mice compared to WT mice. In both genotypes after IRI, we also observed decreased protein level of Spns2. Results of plasma creatinine and BUN confirmed that deletion of Spns2 from renal proximal tubules exert significant protection from IRI. Plasma creatinine: 1.13±0.19 mg/dl and 0.36±0.06 mg/dl, P<***, and BUN: 112.8±10.10 mg/dl and 48.33±5.24 mg/dl, P<**** for WT and PT-KO mice, respectively (n=6). H&E staining and ATN scores (42.63±9.14 and 9.69±2.18 for WT and PT-KO mice, P<**) provided additional evidence of severe damage to proximal tubules of WT mice compared to PT-KO mice after IRI.

Conclusion

Our results suggest that SPNS2 can serve as a potential target to prevent acute kidney injury. However, more studies are necessary to elucidate the SPNS2 signaling pathway.

Funding

  • NIDDK Support