Lack of endothelium‐derived ET‐1 accelerates diabetes‐mediated renal damage in female, but not male, mice

Abstract

Premenopausal females have smaller incidence and slower progression of kidney disease than males; however, diabetes‐induced kidney damage progresses similarly in both sexes. The vasoactive peptide endothelin‐1 (ET‐1) is upregulated in patients and animal models of diabetic nephropathy (DN), yet the specific role of endothelium‐derived ET‐1 in the development of DN remains unclear. These studies were designed to examine the role of vascular ET‐1 in diabetic kidney disease, and to determine if it is responsible for the loss of renal protection in diabetic females. Hyperglycemia was induced in male and female vascular endothelial cell ET‐1 knockout (VEET KO) and floxed mice via STZ (50 mg/kg i.p., 5 consecutive days). After 10 weeks of diabetes, urine and kidneys were collected and markers of glomerular damage, apoptosis (TUNEL assay) and immune cell infiltration were assessed. Histological examination revealed no significant differences in glomerular injury among the groups. However, in response to diabetes, female VEET KO mice presented significantly greater urinary protein excretion (6.0 ± 1.7 vs. 2.4 ± 0.8 mg/day; p<0.05; n=5–7/group) and cortical tubule dilation than diabetic male VEET KO mice. Albumin excretion and renal apoptosis were not significantly different between sexes or genotypes. Both diabetic female genotypes presented similar macrophage influx in renal cortex (VEET KO vs. floxed: 8.0 ± 0.8 vs. 7.9 ± 1.0 ED1+cells/field; n=9/group), and these values were significantly greater than diabetic males (VEET KO vs. floxed: 2.8 ± 0.9 vs. 3.7 ± 0.6 ED‐1+ cells/field; p<0.05; n=4–5/group). In addition, absence of vascular ET‐1 in females led to increased T cell infiltration in cortex (VEET KO vs. floxed: 8.7 ± 1.2 vs. 5.2 ± 0.4 CD3+ cells/field; p<0.05; n=9/group), but not in males (VEET KO vs. floxed: 5.7 ± 0.9 vs. 4.6 ± 1.0 cells/field; n=4–5/group). In conclusion, lack of endothelium‐derived ET‐1 accelerates the development of diabetes‐induced kidney damage in female, but not male, mice. These results highlight the protective role that vascular ET‐1 plays in females, but not males, against the development of DN.Support or Funding InformationFunded by NIH T32 DK007545 to CDM and P01 HL95499 and P01 HL69999 and HL136936 to DMP and JSP.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.