Abstract
Activation of the renin angiotensin system plays a pivotal role in the regulation of blood pressure, which is mainly attributed to the formation of angiotensin-II (Ang II). The actions of Ang II are mediated through binding to the Ang-II type 1 receptor (AT1R) which leads to increased blood pressure, fluid retention, and aldosterone secretion. In addition, Ang II is also involved in cell injury, vascular remodeling, and inflammation. The actions of Ang II could be antagonized by its conversion to the vasodilator peptide Ang (1–7), partly generated by the action of angiotensin converting enzyme 2 (ACE2) and/or neprilysin (NEP). Previous studies demonstrated increased urinary ACE2 shedding in the db/db mouse model of diabetic kidney disease. The aim of the study was to investigate whether renal and urinary ACE2 and NEP are altered in the 2K1C Goldblatt hypertensive mice. Since AT1R is highly expressed in the kidney, we also researched the effect of global deletion of AT1R on renal and urinary ACE2, NEP, and kidney injury marker (KIM-1). Hypertension and albuminuria were induced in AT1R knock out (AT1RKO) and WT mice by unilateral constriction of the renal artery of one kidney. The 24 h mean arterial blood pressure (MAP) was measured using radio-telemetry. Two weeks after 2K1C surgery, MAP and albuminuria were significantly increased in WT mice compared to AT1RKO mice. Results demonstrated a correlation between MAP and albuminuria. Unlike db/db diabetic mice, ACE2 and NEP expression and activities were significantly decreased in the clipped kidney of WT and AT1RKO compared with the contralateral kidney and sham control (p < 0.05). There was no detectable urinary ACE2 and NEP expression and activity in 2K1C mice. KIM-1 was significantly increased in the clipped kidney of WT and AT1KO (p < 0.05). Deletion of AT1R has no effect on the increased urinary KIM-1 excretion detected in 2K1C mice. In conclusion, renal injury in 2K1C Goldblatt mouse model is associated with loss of renal ACE2 and NEP expression and activity. Urinary KIM-1 could serve as an early indicator of acute kidney injury. Deletion of AT1R attenuates albuminuria and hypertension without affecting renal ACE2, NEP, and KIM-1 expression.
Highlights
Chronic kidney disease (CKD) and end stage renal disease (ESRD) remain one of the major worldwide public health problems with increasing prevalence (Murphy et al, 2016)
We investigated the impact of global deletion of the Ang-II type 1 receptor (AT1R) on intrarenal angiotensin converting enzyme 2 (ACE2), NEP, and the known marker of acute kidney marker, Kidney injury molecule-1 (KIM-1)
The present study demonstrates the major new finding that 2K1C Goldblatt renovascular hypertensive model in WT and AT1a receptor knocked out (AT1KO) mice is associated with a significant loss of renal ACE2 and NEP protein expression and activity
Summary
Chronic kidney disease (CKD) and end stage renal disease (ESRD) remain one of the major worldwide public health problems with increasing prevalence (Murphy et al, 2016). Our previous study in the 2K1C Goldblatt hypertensive mice showed loss of the Ang-(1–7) forming enzyme prolyl carboxypeptidase which could impair the degradation of renal Ang II and contribute to kidney injury (Grobe et al, 2015). In the present study, we attempted to induce renovascular hypertension and albuminuria in AT1KO mice to investigate the role of AT1R and hypertension on the Ang- (1–7) forming enzymes, ACE2 and NEP, and on the known biomarkers of acute kidney injury, KIM-1. The rationale of our hypothesis was based in part on our previous studies where there was increased shedding of ACE2 in the mouse model of diabetic kidney disease (Chodavarapu et al, 2013; Salem et al, 2014; Somineni et al, 2014). Urine samples from db/db were analyzed for ACE2 in parallel to 2K1C Goldblatt mouse model of renovascular hypertension
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