Gender difference and sex hormone production in rodent renal ischemia reperfusion injury and repair

Abstract

Background: Several lines of evidence suggest a protective effect of female sex hormones in several organs subjected to ischemia-reperfusion injury. The aim of the study was to investigate sex hormone production in male rats after a renal ischemia-reperfusion sequence and analyze the influence of gender differences on tissue remodelling during the recovery process.

Method: Age-matched sexually mature male and female rats were subjected to 60 min of renal unilateral ischemia by pedicle clamping with contralateral nephrectomy and followed for 1 or 5 days after reperfusion. Plasma creatinine, systemic testosterone, progesterone and estradiol levels were determined. Tubular injury, cell proliferation and inflammation, were evaluated as well as proliferating cell nuclear antigen, vimentin and translocator protein (TSPO) expressions by immunohistochemistry.

Results: After 1 and 5 days of reperfusion, plasma creatinine was significantly higher in males than in females, supporting the high mortality in this group. After reperfusion, plasma testosterone levels decreased whereas estradiol significantly increased in male rats. Alterations of renal function, associated with tubular injury and inflammation persisted during the 5 days post-ischemia-reperfusion, and a significant improvement was observed in females at 5 days of reperfusion. Proliferating cell nuclear antigen and vimentin expression were upregulated in kidneys from males and attenuated in females, in parallel to injury development. TSPO expression was transiently increased in proximal tubules in male rats.

Conclusions: After ischemia, renal function recovery and tissue injury is gender-dependent. These differences are associated with a modulation of sex hormone production and a modification of tissue remodeling and proliferative cell processes.

Figure 1

Renal histological evaluation by light microscopy (Periodic Acid-Schiff, ×400). Proximal tubular epithelial cell injury in kidneys from male (A, B, C) and female rats (D, E, F): basal conditions (A and D), after ischemia followed by 1 (B and E) or 5 days of reperfusion (C and F). pct: proximal convoluted tubule; dct: distal convoluted tubule; cd: cell detachment.

Figure 2

Interstitial inflammatory changes: In all times studied, CD3+ T lymphocytes are the major inflammatory cell population. A; Kidney from Rat Male at Day 5. B; Kidney from Female Rat At Day 5. Magnification ×100.

Figure 3

Representative proximal tubular PCNA staining (arrow). Kidneys from male (A, B) and female rats (C, D); after ischemia followed by 1 (A, C) or 5 days of reperfusion (B, D) (Magnification × 200).

Figure 4

Representative vimentin expression (arrow). Kidneys from male (A, B) and female rats (C, D); after ischemia followed by 1 (A, C) or 5 days of reperfusion (B, D) (Magnification × 200).

Figure 5

Representative renal TSPO staining in the outer medulla in kidneys from male (A, B) and female rats (C, D); after ischemia followed by 1 (A, C) or 5 days of reperfusion (B, D) (Magnification ×100). At Day 1, Kidneys from male rats exhibited a faint transient cytoplasm staining in proximal tubule epithelial cells. pct: proximal convoluted tubule; dct: distal convoluted tubule.