ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: FR-PO696

Therapeutic Blocking of NPRC, a Podocyte-Expressed Target, Is Kidney Protective in ZSF1 Rats

Session Information

Category: Glomerular Diseases

  • 1304 Glomerular Diseases: Podocyte Biology

Authors

  • Lal, Mark, AstraZeneca Pharmaceuticals LP, Gothenburg, Sweden
  • Dabaghie, Dina, Karolinska Institutet, Stockholm, Stockholm, Sweden
  • Charrin, Emmanuelle, Karolinska Institutet, Stockholm, Stockholm, Sweden
  • Tonelius, Pernilla, AstraZeneca Pharmaceuticals LP, Gothenburg, Sweden
  • Rosengren, Birgitta E., AstraZeneca Pharmaceuticals LP, Gothenburg, Sweden
  • Granqvist, Anna, AstraZeneca Pharmaceuticals LP, Gothenburg, Sweden
  • Patrakka, Jaakko, Karolinska Institutet, Stockholm, Stockholm, Sweden
Background

Increasing natriuretic peptide (NP) levels can be achieved by neprilysin inhibition and is a clinically validated therapeutic strategy for heart failure, when combined with an angiotensin receptor blocker. An equally important and fundamental determinant of NP levels is contributed to by the NP clearance receptor, NPRC, a membrane protein abundantly expressed in the kidney. In this study, we aimed to elucidate the role of NPR3 in the pathogenesis of glomerulopathies.

Methods

Renal expression of NPR3 was studied using qPCR, scRNAseq and immunohistochemistry. The functional role of NPRC was analyzed using a novel mouse line in which NPRC was genetically inactivated specifically in podocytes (NPRC podKO). NPRC was targeted pharmaceutically using an NPRC blocking peptide in a rat model of DN (uninephrectomized obese ZSF-1 rats (UNx ZSF-1 rats)), followed by studies in a mouse glomerulopathy model.

Results

NPRC was highly and specifically expressed by podocytes of the glomerulus. NPRC podKO mice showed normal kidney morphology and function and NPRC-deficiency did not readily affect the outcome of an acute mouse glomerulopathy model. In diabetic UNx ZSF-1 rats, pharmaceutical blocking of NPRC activity resulted in increased urinary and plasma cGMP levels, indicative of successful target engagement and elevated NPs. Diabetic rats treated only with NPR3 blocker showed limited impact on readouts of renal injury. However, when NPRC blocking was combined with losartan (angiotensin receptor blocker), it potentiated significantly the ameliorative effects on albuminuria and glomerular sclerosis. In line with this, NPRC blocking showed reno-protective effects in a mouse glomerulopathy model as shown by decreased glomerulosclerosis and reduced podocyte loss.

Conclusion

NPRC is highly expressed by podocytes and blocking its clearance activity appears to contribute to reno-protective effects in DN. Additional studies are needed to understand the molecular mechanisms of NP-signaling in the glomerulus and to explore the extent to which local paracrine and systemic NPRC blocking may contribute to functional benefit in kidney disease.

Funding

  • Commercial Support