Abstract: SA-PO388

suPAR Induces Proteinuria in Solitary Functioning Kidney Models

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 301 CKD: Risk Factors for Incidence and Progression

Authors

  • Wang, Xuexiang, Rush University Medical Center, Chicago, Illinois, United States
  • Garrett, Michael R., University of Mississippi Medical Center, Jackson, Mississippi, United States
  • Wei, David Changli, Rush University Medical Center, Chicago, Illinois, United States
  • Reiser, Jochen, Rush University Medical Center, Chicago, Illinois, United States
Background

Single functioning kidney (SFK) is expected in one out of 1500 births, and it causes renal injury before adulthood in over 50% of those affected. Similarly, kidney donors may have increased risk for future CKD. The underlying mechanisms and related biomarkers are still lacking. The soluble urokinase receptor (suPAR) is a circulating factor implicated in FSGS and is also a potent biomarker for predicting CKD incidence and progression. In this study, we explore the effect of elevated circulating suPAR on proteinuria development in three different rodent models of SFK.

Methods

Uninephrectomy and sham surgeries were performed on C57B/6 (B/6) mice, suPAR transgenic models or littermate controls. Minipumps with three different concentrations of LPS were implanted subcutaneously in B/6 mice only. Proteinuria and/or suPAR were followed weekly for 4 weeks. In the HSRA spontaneous one-kidney rat model, the recombinant human suPAR protein was injected intravenously into HSRA single kidney rats (HSRA-S) and two-kidney controls (HSRA-C). Proteinuria was measured 24 hours after. The activity of beta3 integrin in podocytes was determined by AP5 immunostaining.

Results

In B/6 mice, all three concentrations of LPS infusion resulted in increased level of serum and urine suPAR. Interestingly, nephrectomy resulted in higher serum suPAR and proteinuria, compared to the sham two-kidney groups. In contrast, uPAR deficient SFK mice are protected from LPS induced proteinuria. Nephrectomized suPAR transgenic mice demonstrated slowly increased proteinuria over 4 weeks of time, while the littermate control mice with nephrectomy showed no change in the urinary protein. HSRA-S rats revealed an increase of proteinuria compared to HSRA-C after the recombinant human suPAR injection. Moreover, the activity of the suPAR receptor beta3 integrin was significantly increased in the kidney of HSRA-S rats following administration of suPAR.

Conclusion

Increased circulating suPAR levels, either induced by LPS, or from suPAR transgenic models or extrinsically injected, induce proteinuria in uninephrectomized mice or rats with unilateral kidney agenesis, when compared to their two-kidney controls. These findings suggest an important role of suPAR in SFK kidney, possibly in kidney donors. Monitoring circulating suPAR levels might be important in understanding the pathogenesis and risk-control for patients with SFK.

Funding

  • NIDDK Support