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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


  • 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

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.


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.


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.


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.


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