Abstract: TH-OR077
Evidence for Female Protection from Kidney Injury during Angiotensin II Hypertension
Session Information
- Hypertension and CVD: Basic Mechanisms
October 25, 2018 | Location: 6F, San Diego Convention Center
Abstract Time: 05:42 PM - 05:54 PM
Category: Hypertension and CVD
- 1403 Hypertension and CVD: Mechanisms
Authors
- Shirvani, Borna S., Keck School of Medicine of USC, Los Angeles, California, United States
- Veiras, Luciana C., Keck School of Medicine of USC, Los Angeles, California, United States
- Ralph, Donna, Keck School of Medicine of USC, Los Angeles, California, United States
- Lei, Hillmin, Keck School of Medicine of USC, Los Angeles, California, United States
- McDonough, Alicia A., Keck School of Medicine of USC, Los Angeles, California, United States
Background
To address resistance to cardiovascular and kidney disease in females (F) vs. males (M), we recently defined sexual dimorphisms in renal transporters’ abundance and distribution along the nephron. We reported lower proximal and higher distal Na+ transporters’ abundance and activity along nephrons of F vs. M rats and mice. This study aimed to examine susceptibility to renal injury during Ang II Hypertension (AngII-HTN) in F vs. M Sprague Dawley rats.
Methods
Rats were either implanted with osmotic minipumps that infused 400 ng/kg/min AngII for 2 weeks or sham operated (n=6/group). Systolic blood pressure (tail-cuff) increased to 190 mmHg in both sexes. Urine was collected overnight in metabolic cages before sacrifice after which blood and kidney were collected. Quantitative immunoblotting was used to assess protein levels of kidney injury molecule-1 (KIM-1), angiotensinogen (aogen) and plasmin in urine and/or renal cortex; serum and urine albumin were quantified via ELISA and BCG method, respectively, and confocal immunohistochemistry (IHC) used to detect endocytosed albumin.
Results
Urinary albumin, similar at baseline in M and F, was 10-fold higher in M vs. F during AngII-HTN (p<0.001) associated with a 10% fall in serum albumin in M (p=0.05, no change in F). Urinary KIM-1, aogen and plasmin were markedly increased in M during AngII-HTN while near undetectable in F. Higher urinary plasmin in M vs. F correlated with twice as much cleaved (activated) epithelial Na+ channel gamma subunit during AngII-HTN (p<0.0001). In renal cortex homogenates at baseline, KIM-1, aogen and megalin were higher in M vs F; during AngII-HTN cortical megalin increased in F only while KIM-1 and a’ogen were unchanged. AngII-HTN increased cortical albumin in both sexes and endocytosed albumin was evident by IHC in M PT but not F.
Conclusion
Despite similar increases in blood pressure, M vs. F rats exhibit greater susceptibility to renal injury during AngII-HTN, evident as greatly increased urinary albumin, KIM-1, aogen, plasmin associated ENaC activation, and endocytosed PT albumin.
Funding
- NIDDK Support