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Kidney Week

Abstract: SA-PO829

Targeting Pathologic Gβγ-GRK2 Signaling in CKD

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Rudomanova, Valeriia, Cincinnati Children''s Hospital Medical Center, Cincinnati, Ohio, United States
  • Valiente-Alandi, Iñigo, Cincinnati Children''s Hospital Medical Center, Cincinnati, Ohio, United States
  • Ma, Qing, Cincinnati Children's Hospital, Cincinnati, Ohio, United States
  • Devarajan, Prasad, Cincinnati Children's Hospital, Cincinnati, Ohio, United States
  • Blaxall, Burns C., Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
Background

Chronic kidney disease (CKD) is a progressive deterioration of renal function characterized by replacement of functional renal parenchyma with fibrotic tissue. Our group recently reported the beneficial effects of attenuating Gβγ-G-protein coupled receptor kinase 2 (GRK2) signaling in the ischemia/reperfusion murine model of acute kidney injury (AKI). In this study, we tested the hypothesis that inhibiting Gβγ-GRK2 signaling might bestow a renoprotective effect in animal models of chronic kidney injury.

Methods

Research animals (C57Bl/6 10 week old male mice) were subjected to unilateral ischemia-reperfusion (UIR, 30min) or sham surgery followed by 14 days of reperfusion. The Gβγ-GRK2 small molecule inhibitor, Gallein, or Vehicle (PBS) were given once daily i.p. beginning 7 days after the injury and continued until sacrifice. GRK2 expression was also evaluated in human kidney biopsies and whole murine kidney lysates by RT-qPCR and Western blot.

Results

We first identified a significant elevation of GRK2 mRNA (8 normal vs 10 dialysis, 1.9 fold increase, P=0.01) and protein (9 normal vs 10 dialysis, 20.6 fold increase, P=0.02) expression in biopsies obtained from dialysis patients vs normal human kidney biopsies. In the UIR model of CKD, GRK2 transcript expression positively correlated with Lipocalin 2 (NGAL) transcript, a clinically used renal injury marker (R squared=0.7488, P<0.0001). Small molecule inhibition of Gβγ-GRK2 significantly alleviated renal fibrosis as assessed by Picrosirius red staining (Sham, UIR+Vehicle, UIR+Gallein, n=8 per group, % fibrosis mean 1.422, 10.08, 4.665, respectively, P<0.0001), accompanied by a decline in NGAL gene expression.

Conclusion

Our results identify Gβγ-GRK2 signaling as a potential mediator of renal tubular injury and fibrosis and a promising target in CKD.

A: Pisrosirius Red staining (red color stains fibrotic areas); B: Hematoxilin & Eosin staining.

Funding

  • Other NIH Support