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Kidney Week

Abstract: SA-PO270

RXFP1, the Relaxin Receptor, Is a Therapeutic Target Expressed in the Human Kidney, Not Rodent

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Lal, Mark, AstraZeneca PLC, Gothenburg, Sweden
  • Eddy, Sean, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Hodgin, Jeffrey B., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Althage, Magnus, AstraZeneca PLC, Gothenburg, Sweden
  • Laerkegaard Hansen, Pernille B., AstraZeneca PLC, Gothenburg, Sweden
  • Patrakka, Jaakko, Karolinska Institutet, Stockholm, Stockholm, Sweden
  • Kretzler, Matthias, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
Background

RXFP1 is a G-protein coupled receptor (GPCR) potently agonized by its cognate ligand, relaxin. Historically named the pregnancy hormone following its identification and physiological description in rodents, relaxin is broadly recognized as a circulating hormone possessing several potentially clinically relevant cardiovascular-modulating and anti-fibrotic properties. It has long been recognized that there is remarkable diversity among species with regard to tissue source, regulation of synthesis and secretion, and physiological effects of relaxin. On the other hand, there is limited and inadequate understanding of RXFP1’s tissue and cell expression across species, especially human.

Methods

Here, we describe the human target validation of RXFP1 in human kidney and highlight striking differences with rodent.

Results

As opposed to mouse and rat kidney, where RXFP1 is poorly expressed, RXFP1 is identified as one of the most highly expressed GPCRs in human glomeruli. Specifically, by single cell RNAseq, in situ hybridization and immunohistochemistry, we identify glomerular endothelial cells as the principal cell type expressing RXFP1. Through extensive analysis of human kidney expression data sets from patient biopsies, we find that RXFP1 expression correlates with kidney function and disease progression. We identified a 428 gene RXFP1 co-expression network (R>0.6, FDR<0.05) that was enriched for an endothelial cell gene signature.

Conclusion

These observations provide a vital foundation to building our pharmacologic understanding of relaxin/RXFP1 function in human and suggest that kidney-intrinsic target engagement may mechanistically explain the renal hemodynamic actions noted in clinical trials with relaxin. Great care needs to be taken to avoid conflation of relaxin’s diverse physiological effects observed in species where RXFP1 cellular expression is not congruent with human.

Funding

  • Other NIH Support – AstraZeneca