Circulatory and renal consequences of pregnancy in diabetic NOD mice

Abstract

Objectives: Women with diabetes have elevated gestational risks for severe hemodynamic complications, including preeclampsia in mid- to late pregnancy. This study employed continuous, chronic radiotelemetry to compare the hemodynamic patterns in non-obese diabetic (NOD) mice who were overtly diabetic or normoglycemic throughout gestation. We hypothesized that overtly diabetic, pregnant NOD mice would develop gestational hypertension and provide understanding of mechanisms in progression of this pathology.

Study design: Telemeter-implanted, age-matched NOD females with and without diabetes were assessed for six hemodynamic parameters (mean, systolic, diastolic, pulse pressures, heart rate and activity) prior to mating, over pregnancy and over a 72 h post-partum interval. Urinalysis, serum biochemistry and renal histopathology were also conducted.

Results: Pregnant, normoglycemic NOD mice had a hemodynamic profile similar to other inbred strains, despite insulitis. This pattern was characterized by an interval of pre-implantation stability, post implantation decline in arterial pressure to mid gestation, and then a rebound to pre-pregnancy baseline during later gestation. Overtly diabetic NOD mice had a blood pressure profile that was normal until mid-gestation then become mildly hypotensive (-7 mmHg, P < 0.05), severely bradycardic (-80 bpm, P < 0.01) and showed signs of acute kidney injury. Pups born to diabetic dams were viable but growth restricted, despite their mothers' failing health, which did not rebound post-partum (-10% pre-pregnancy pressure and HR, P < 0.05).

Conclusions: Pregnancy accelerates circulatory and renal pathologies in overtly diabetic NOD mice and is characterized by depressed arterial pressure from mid-gestation and birth of growth-restricted offspring.

Figure 1

Neonatal outcomes of normoglycemic and diabetic NOD dams. Average litter size for normoglycemic (n=9, black bar) and diabetic (n=5, white bar) dams. Average weight at birth for normoglycemic (n=76, black bar) and diabetic (n=31, white bar) pups. *P<0.01.

Figure 2

Pressures of normoglycemic (n=6, black circles) and diabetic (n=5, white circles) over gestation. A) Mean arterial pressure (MAP). B) Systolic arterial pressure (SAP). C) Diastolic arterial pressure (DAP). D) Pulse pressure (PP). Data is averaged over a 24-hour period, presented as mean±SEM. *P<0.01 compared to baseline (both groups), #P<0.05 compared to diabetic NOD baseline.

Figure 3

A) Heart rate (HR) and B) activity level of normoglycemic (n=6, black circles) and diabetic (n=5, white circles) over gestation. Data is averaged over a 24-hour period, presented as mean±SEM. *P<0.01 compared to baseline.

Figure 4

Microalbumin:creatinine from spot urine samples from normoglycemic (black bar) and diabetic (white bar) mice. Time points examined are non-pregnant (NP), gestation day (gd)1-4, gd5-9, gd10-14, gd15-19 and post-partum (PP). N=4–6 animals per time point, with minimum three samples/animal/time point. *P<0.01 vs. normoglycemic NOD mice, #P<0.05 vs. NP diabetic NOD mice. ΦP<0.01 vs. gd15-19 normoglycemic NOD mice.

Figure 5

Renal histology of 96-hr post-partum NOD mice. A) normoglycemic NOD mouse B) Diabetic NOD mouse. Images highlight a representative area of the renal cortex (n=5/condition). H&E staining showed normal histopathology in normoglycemic mice. Diabetic mice did not exhibit typical changes consistent with diabetic nephropathy, in particular no glomerulosclerosis (black arrows). However, kidneys from diabetic mice showed evidence for the presence of acute kidney injury (AKI), such as dilated proximal tubules with loss of brush border (#) and overall moderate vacuolization of tubular epithelial cells.