Deletion of the Npr3 gene increases severity of acute lung injury in obese mice

Abstract Previous studies have shown that atrial natriuretic peptide (ANP) attenuates agonist‐induced pulmonary edema and that this effect may be mediated in part by the ANP clearance receptor, natriuretic peptide receptor‐C (NPR‐C). Obesity has been associated with lower plasma ANP levels due to increased expression of NPR‐C, and with decreased severity of acute lung injury (ALI). Therefore, we hypothesized that increased expression of NPR‐C may attenuate ALI severity in obese populations. To test this, we examined ALI in Npr3 wild‐type (WT) and knockout (KO) mice fed normal chow (NC) or high‐fat diets (HFD). After 12 weeks, ALI was induced with intra‐tracheal administration of Pseudomonas aeruginosa strain 103 (PA103) or saline. ALI severity was determined by lung wet‐to‐dry ratio (W/D) along with measurement of cell count, protein levels from bronchoalveolar lavage fluid (BALF), and quantitative polymerase chain reaction was performed on whole lung to measure cytokine/chemokine and Npr3 mRNA expression. ANP levels were measured from plasma. PA103 caused ALI as determined by significant increases in W/D, BALF protein concentration, and whole lung cytokine/chemokine expression. PA103 increased Npr3 expression in the lungs of wild‐type (WT) mice regardless of diet. There was a nonsignificant trend toward increased Npr3 expression in the lungs of WT mice fed HFD versus NC. No differences in ALI were seen between Npr3 knockout (KO) mice and WT‐fed NC, but Npr3 KO mice fed HFD had a significantly greater W/D and BALF protein concentration than WT mice fed HFD. These findings support the hypothesis that Npr3 may help protect against ALI in obesity.