Effects of Angiotensin II Type 1A Receptor on ACE2, Neprilysin and KIM-1 in Two Kidney One Clip (2K1C) Model of Renovascular Hypertension

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.

Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting

“…Although this suggests that neprilysin is crucial for Ang-(1-7) formation at renal tissue sites, neprilysin inhibition in rats did not alter renal Ang-(1-7) levels ( Roksnoer et al, 2015 ). In 2-kidney, 1-clip Goldblatt hypertensive mice, neprilysin was markedly reduced in the clipped kidney ( Alawi et al, 2021 ), whereas in the kidney of diabetic db/db mice (a type 2 diabetes model), neprilysin was also significantly decreased ( Alawi et al, 2020 ).…”

“…Increased ACE2 levels, by contrast, were found in tubules from young SHRs prior to the onset of hypertension, which then declined with the onset of hypertension ( Tikellis et al, 2006 ). In the 2-kidney, 1-clip mouse model of hypertension, ACE2 and neprilysin expression decreased in parallel ( Alawi et al, 2021 ). Similar to the data in animal models, biopsies from patients with hypertensive nephropathy examined by immunohistochemistry show a marked decrease of ACE2 staining in tubules ( Koka et al, 2008 ).…”

A New Approach for the Development of Multiple Cardiovascular Risk Factors in Two Rat Models of Hypertension

“…By clipping the renal artery, the renin–angiotensin system is activated, inducing the upregulation of renin release in the first weeks after surgery and leading to increases in angiotensin II and hypertension. Constriction of the renal arteries closely mimics the pathophysiology of their human analog, but renovascular hypertension represents only a small fraction of manifestations of clinical hypertension [ 13 , 14 ]. Spontaneous hypertensive rats are the most widely used animal model of essential hypertension.…”

Analysis of mRNA and protein kidney injury Molecule-1 (KIM-1) expression in a kidney model during the initiation phase of ischemia reperfusion injury

“…Brief ischemia (10 min) will result in a 20% decrease in renal ATP levels. In reperfusion, injury is increased as a result of oxidative stress [ [6] , [7] , [8] ], inflammation [ [9] , [10] , [11] ] and “ no-reflow ” phenomenon [ [14] , [15] , [16] , 18 , 26 ]. The causes of “no-reflow” are mainly endothelial oxidative stress, fibrinogen thromboembolic formation, neutrophil adhesion to capillary endothelium, endothelial dysfunction, increased vasoconstrictor, and decreased vasodilator.…”

“…Therefore, renal ischemia-reperfusion injury (IRI) contributes to increased morbidity and mortality [ 5 ]. On the other hand, ischemia-reperfusion (IR) injury causes acute tubular necrosis (ATN) through oxidative stress mechanism [ [6] , [7] , [8] ], inflammation [ [8] , [9] , [10] , [11] , [12] , [13] ], and the “no-reflow” phenomenon [ [14] , [15] , [16] , [17] , [18] ].…”