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Sex differences in the activation of renal cell death pathways in diabetic vascular endothelial cell ET‐1 knockout mice
Author(s) -
De Miguel Carmen,
Martinez Vianna G.,
Almutlaq Rawan,
Pollock David M.,
Pollock Jennifer S.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.04708
Subject(s) - medicine , endocrinology , nephrin , glomerulosclerosis , excretion , diabetic nephropathy , diabetes mellitus , kidney , streptozotocin , kidney disease , proteinuria , podocyte
Contrary to other renal diseases that progress faster in males than females, diabetic kidney disease advances at a similar rate in both sexes. The role of endothelium‐derived ET‐1 in the development of diabetic nephropathy remains unclear. These studies were designed to examine the role of vascular ET‐1 in diabetic kidney disease, and to determine if it plays a role in 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 ET‐1 mice with streptozotocin (STZ, 50 mg/kg i.p., 5 consecutive days). 10 weeks later, urine and kidneys were collected and kidney damage and cortical expression of cell death pathways were assessed. In response to diabetes, female VEET KO mice displayed greater interstitial fibrosis and cortical tubule dilation. Glomerulosclerosis, GFR, NGAL excretion and nephrin excretion were not different between sexes or genotypes. Interestingly, lack of vascular ET‐1 led to decreased albumin excretion with diabetes, although no sex difference was found (VEET KO vs. floxed ET‐1: 51.6 ± 4.3 vs. 104.1 ± 3.3 mg/day, p<0.05; n=5–7/group). We also found a sex effect in protein and KIM‐1 excretions, with greater excretion of these parameters in females than males (females vs. males, protein: 3.8 ± 0.6 vs. 1.8 ± 0.1 mg/day; KIM‐1: 3.5 ± 0.0 vs. 1.6 ± 0.5 pg/day; p<0.05; n=5–7/group). Compared to diabetic male VEET KO mice, absence of vascular ET‐1 in females resulted in the cortical upregulation of 48 genes involved in cell death pathways (16 genes each for autophagy, necrosis and pro‐apoptosis; 2–4 fold increase, p<0.05, n=3/group). These results highlight the protective role that vascular ET‐1 plays in females, but not males, against the development of diabetic nephropathy. Support or Funding Information Funded by NIH K01HL145324 and UAB Diabetes Research Center Pilot Project grant to CDM, and UAB KURE R25 DK115353 to VGM and JSP.