Glucose homeostasis is impaired in Guanylyl Cyclase/Natriuretic Peptide Receptor‐A Gene‐Knockout and Gene‐Duplication Mutant Mice

Abstract

Atrial and brain natriuretic peptides (ANP and BNP) are produced in the heart, regulate blood pressure (BP) and fluid homeostasis through vasodilatory and diuretic actions. Both ANP and BNP act by binding to guanylyl cyclase/natriuretic peptide receptor‐A (GC‐A/NPR‐A). Systemic disruption of Npr1(encoding GC‐A/NPRA) leads to volume overload, high BP, and congestive heart failure. However, the underlying mechanisms are not yet precisely determined. The aim of this study was to investigate whether Npr1plays a critical role in regulating glucose homeostasis in Npr1 gene‐disrupted mice. The adult male and female (16‐18 wk) Npr1 gene‐knockout haplotype (Npr1+/‐, 1‐copy), wild‐type (Npr1+/+, 2‐copy), and gene‐duplicated (Npr1+ +/+ +, 4‐copy) mice were fasted for 16 h and given free access to water. The glucose administration was done both orally and intraperitoneally (IP: 2 g/kg body weight) in mice to determine oral glucose tolerance test (OGTT) and IP glucose tolerance test (IPGTT). The glucose levels in blood were determined by performing tail bleeds at 0, 15, 30, 60, 90, and 120 min using the AlphaTRAK blood glucose monitoring system (Zoetis Inc, Kalamazoo, MI). Systolic BP (SBP) was determined by non‐invasive computerized tail‐cuff method (Visitech 2000). The results showed that the blood glucose level was elevated to the maximum value at 15 min after glucose administration. Glucose levels were declined to near base line at 120 min in 2 copy mice (OGTT: 102 ± 3 mg/dL in male and 97 ± 4 mg/dL in female, IPGT: 101 ± 4 mg/dL in male and 96 ± 3 mg/dL in female). However, in 1‐copy mice, the blood glucose levels remained elevated even after 120 min (OGTT: 248 ± 5 mg/dL in male and 226 ± 3 mg/dL in female, IPGT: 254 ± 4 mg/dL in male and 229 ± 5 mg/dL in female) compared with 2‐copy mice. The blood glucose levels were also significantly lower at 120 min in 4‐copy mice (OGTT: 77 ± 4 mg/dL in male and 74 ± 3 mg/dL in female, IPGT: 75 ± 3 mg/dL in male and 71 ± 2 mg/dL in female) compared with 2‐copy mice. SBP was significantly greater in 1‐copy mice (137 + 4 mmHg in male and 126 + 3 mmHg in female) than 2‐copy mice (100 + 2 mmHg in male and 91 + 2 mmHg in female). SBP was significantly lower in 4‐copy mice (83 + 2 mmHg in male and 77 + 2 mmHg in female) than 2‐copy mice. OGTT showed a significantly lower level of maximal blood glucose compared with IPGTT. The findings of the present study suggest that Npr1 plays a critical role in the regulation of glucose homeostasis and the loss of Npr1 significantly increases the glucose levels in mutant animals.