Early life stress induces renal dysfunction in adult male rats but not female rats

Abstract

Maternal separation (MatSep) is a model of behavioral stress during early life. We reported that MatSep exacerbates ANG II-induced hypertension in adult male rats. The aims of this study were to determine whether exposure to MatSep in female rats sensitizes blood pressure to ANG II infusion similar to male MatSep rats and to elucidate renal mechanisms involved in the response in MatSep rats. Wistar Kyoto (WKY) pups were exposed to MatSep 3 h/day from days 2 to 14, while control rats remained with their mothers. ANG II-induced mean arterial pressure (MAP; telemetry) was enhanced in female MatSep rats compared with control female rats but delayed compared with male MatSep rats. Creatinine clearance (Ccr) was reduced in male MatSep rats compared with control rats at baseline and after ANG II infusion. ANG II infusion significantly increased T cells in the renal cortex and greater histological damage in the interstitial arteries of male MatSep rats compared with control male rats. Plasma testosterone was greater and estradiol was lower in male MatSep rats compared with control rats with ANG II infusion. ANG II infusion failed to increase blood pressure in orchidectomized male MatSep and control rats. Female MatSep and control rats had similar Ccr, histological renal analysis, and sex hormones at baseline and after ANG II infusion. These data indicate that during ANG II-induced hypertension, MatSep sensitizes the renal phenotype in male but not female rats.

Fig. 1.

Effect of chronic infusion of ANG II in MAP of control and MatSep female rats. A: ANG II-induced hypertension is delayed and attenuated in female MatSep rats compared with control rats. B: changes in MAP in response to ANG II infusion is greater in female MatSep rats (n = 7) than control female rats (n = 6) in the last 4 days of the infusion period (65 ng/day sc). *P < 0.05 vs. corresponding sex control group, #P < 0.05 vs. corresponding male group.

Fig. 2.

Changes in creatinine clearance (C_Cr) as a parameter of renal function at baseline and after 2 wk of ANG II infusion. A: CCr in male MatSep rats was reduced at baseline. ANG II infusion did not aggravate CCr in MatSep rats significantly. B: female MatSep rats displayed similar CCr than control rats. *P < 0.05 vs. male control group.

Fig. 3.

Renal damage scores in ANG II-infused rats. A: damage in interstitial arteries was exacerbated in male MatSep rats compared with control rats in response to ANG II infusion. B: renal damage in response to ANG II was similar in control and female MatSep rats. Lower panel pictures show representative pictures of glomerulus in male control (C) and MatSep (D) and female control (E), and MatSep (F) rats; interstitial artery in male control (G) and MatSep (H) and female control (I) and MatSep (J) rats. *P < 0.05. TI, tubulointerstitium; IA, interstitial arteries; G, glomerulus; GA, glomerular arteriolae. Score: 0, nil; 1, mild; 2 moderate; 3 severe. Scale bar = 25 μM.

Fig. 4.

Immune cell infiltration in renal medulla and cortex of ANG II-infused rats. A: numbers of CD-68- (macrophages) positive cells were similar in medulla and cortex from control and male MatSep rats. C: numbers of CD-3- (lymphocytes) positive cells were similar in medulla from control and male MatSep rats. CD-3 cells were increased in renal cortex from male MatSep rats compared with control. B and D: cortical and medullary CD-68- and CD-3 positive cells in medulla and cortex from control and female MatSep rats. Representative kidney sections of males (E, F, I, and J) and females (G, H, K, and L). *P < 0.05 vs. male control group.

Fig. 5.

Plasma sex hormone levels in ANG II-infused rats. ANG II infusion significantly reduces Ts levels compared with baseline; however, male MatSep rats presented significantly elevated Ts levels compared with control MatSep rats (A). E₂ levels were below detection in male MatSep rats compared with control rats after ANG II infusion (C). Although ANG II reduced significantly testosterone and estrogen levels in female rats, these levels were similar MatSep and female control rats (B and D). *P < 0.05 vs. ANG II male control group. #P < 0.05 vs. baseline corresponding sex group.

Fig. 6.

Effect of orchidectomy (ORX) on ANG II-induced hypertension. ORX significantly reduced the response to ANG II in control and MatSep rats compared with intact rats. *P < 0.05 vs. intact ANG II control. #P < 0.05 vs. MatSep intact group.