Publication Date

2015

Document Type

Thesis

Committee Members

Mauricio Di Fulvio (Committee Member), Khalid Elased (Advisor), Nadja Grobe (Committee Member)

Degree Name

Master of Science (MS)

Abstract

Activation of the renin angiotensin system (RAS) and increased formation of angiotensin (Ang) II contribute to the progression of chronic kidney disease (CKD). Ang II, the major biologically active peptide of RAS, acts mainly as a vasoconstrictor through binding to the Ang II type 1 receptor (AT1R), which leads to increased blood pressure, fluid retention, and aldosterone secretion. The actions of Ang II are antagonized by its conversion to the vasodilator Ang (1-7), partly generated by the action of angiotensin converting enzyme 2 (ACE2) and/or neprilysin (NEP). The metalloprotease ADAM17 has a crucial role in the shedding of renal ACE2 in diabetic mice model. The two-kidney, one clip (2K1C) Goldblatt model is an experimental approach designed to mimic renovascular hypertension. It consists of the unilateral clamping of the renal artery in one of the kidneys. The aim of this study is to test the hypotheses that: 1) renovascular hypertension and increased albuminuria in the 2K1C model is mediated by AT1AR and 2) up-regulation of renal ADAM17 increase the shedding of renal ACE2 and NEP into the urine. Wild type (WT) and AT1AR knockout (AT1 KO) mice were used to test our hypotheses. Mice were subjected to surgical procedures to implant radio-telemetry transmitters for measurement of blood pressure (BP), followed by induction of renovascular hypertension. BP at baseline was significantly lower in AT1 KO compared to WT mice, whereas in WT 2K1C, BP was significantly higher than controls (p<0.05). However, 2K1C has no effect on BP in AT1 KO mice. Urinary albumin excretion significantly increased in WT 2K1C mice compared to sham -operated ones, while no change was observed in AT1 KO. In addition, a significant reduction of renal ADAM17 and NEP contents was observed in clipped kidney relative to the unclipped and sham kidneys. Western blot analysis showed a significant decrease in renal ACE2, NEP, and ADAM17 protein expression levels in the clipped kidney compared to the unclipped or sham-operated ones. Histological assessment of the kidneys in the 2K1C model revealed significant mesangial expansion and renal fibrosis. Data suggest that renovascular hypertension is mediated by AT1AR and deletion of this receptor attenuates albuminuria in the 2K1C model. In 2K1C, the downregulation of renal and urinary ACE2 and ADAM17 suggest a potential link between ADAM17 and ACE2 shedding in 2K1C mice. Decreased renal NEP in the clipped kidney of 2K1C model may thus worsen kidney injury via impairment of Ang (1-7) formation.

Page Count

91

Department or Program

Department of Pharmacology and Toxicology

Year Degree Awarded

2015

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