Targeting Natriuretic Peptide Receptor 3 (NPR3) to improve renal function in chronic kidney disease

Chronic kidney disease (CKD) is a major medical challenge affecting globally >10% of the population. Treatment options for CKD are limited and often ineffective.

We have discovered that a clearance receptor for natriuretic peptides (NPs), natriuretic peptide receptor 3 (NPR3), is highly produced by renal podocyte cells and that its inactivation (genetically or pharmacologically) promotes local glomerular NP-signaling and has reno-protective effects.

In this study, we aim to: 1) Validate reno-protective effects of NPR3 inhibition by treating several rodent models of CKD with a NPR3 blocking peptide (NPR3i), with the goal of establishing NPR3 as a novel therapeutical target; 2) To identify the mechanism-of-action for NPR3-mediated reno-protection in vivo by analyzing podocyte-specific NPR3 knockout (KO) mouse line challenged with models of CKD.

Key mechanisms identified will be studied further in vitro using immortalized podocyte cell lines; 3) To analyze reno-protective effects of NPR3 inhibition in man by treating human kidney organoids and human precision cut kidney slices under pathological stimuli with NPR3i, with the goal of translating our promising animal data to human kidney tissue.

Key findings will be studied further in cultured human podocytes. To summarize, our overall aim is to analyse whether the targeting of NPR3 can be a novel strategy to treat CKD.