Abstract
Pappa2 (pregnancy associated plasma protein A2) is a protease of insulin-like growth factor binding protein 5 (IGFBP5) which has been primarily studied in pregnancy and post-natal growth. Our recent studies using contiguous congenic strains indicate that Pappa2 is linked to salt-sensitive hypertension in Dahl salt-sensitive (SS) rats. The role of Pappa2 in cardiovascular and renal function has not been studied previously. We therefore mutated Pappa2 in a salt-resistant subcongenic strain 26-P using the CRISPR-Cas9 method. Mutation of the Pappa2 gene resulted in a 60-bp deletion and the absence of the wild type protein in the urine was verified by Western blot analysis. We hypothesized that deletion of Pappa2 in the salt-insensitive strain would return or enhance BP salt-sensitivity as found in SS rats. Both parental rats and weaned offspring were maintained on a 0.4% NaCl diet until 9 weeks of age, then surgically instrumented with radiotelemeters for 24 hr BP recordings obtained while fed 0.4% NaCl and during 21 days of a 4% NaCl diet. Results: Mean 24 hr arterial pressure at 21 days of a 4.0% salt diet was significantly higher (P<0.05) in male Pappa2-/- (164 + 5 mmHg; n=11) compared to Pappa2+/+ WT (137 + 4 mmHg; n=9) rats. Body weight (9 wks) of Pappa2-/- was less (P<0.05) than weight of Pappa2+/+ WT rats (217 + 7 g vs 281 + 11 g). Although less than expected compared to previously studied SS rats, indices of renal injury were only moderately increased in Pappa2-/- compared to Pappa+/+ WT rats including tubular protein casts (6.509 ± 0.789, n=11 vs 3.8 ± 0.718, n=9; P<0.05), cortical T-lymphocyte (CD3 + /mm 2 ; 96.1 ± 9.9, n=11 vs 70.9 ± 6.8, n=9; P=0.06), macrophage (CD68 + /mm 2 ; 74.6 ± 9.4, n=11 vs 47.6 ± 5.2, n=8; P<0.05), and interstitial smooth muscle actin (4.5 ± 0.4, n=11 vs 3.4 ± 0.2, n=8; P<0.05). In summary, the “rescue” of the BP salt-sensitivity trait with mutation of Pappa2 provides the first direct evidence that this gene plays an important role in renal fluid and electrolyte homeostasis and the regulation of arterial pressure.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
