Renal ischemia-reperfusion injury causes hypertension and renal perfusion impairment in the CD1 mice which promotes progressive renal fibrosis

Abstract

Renal ischemia-reperfusion injury (IRI) is a severe complication of major surgery and a risk factor for increased morbidity and mortality. Here, we investigated mechanisms that might contribute to IRI-induced progression to chronic kidney disease (CKD). Acute kidney injury (AKI) was induced by unilateral IRI for 35 min in CD1 and C57BL/6 (B6) mice. Unilateral IRI was used to overcome early mortality. Renal morphology, NGAL upregulation, and neutrophil infiltration as well as peritubular capillary density were studied by immunohistochemistry. The composition of leukocyte infiltrates in the kidney after IRI was investigated by flow cytometry. Systemic blood pressure was measured with a tail cuff, and renal perfusion was quantified by functional magnetic resonance imaging (fMRI). Mesangial matrix expansion was assessed by silver staining. Following IRI, CD1 and B6 mice developed similar morphological signs of AKI and increases in NGAL expression, but neutrophil infiltration was greater in CD1 than B6 mice. IRI induced an increase in systemic blood pressure of 20 mmHg in CD1, but not in B6 mice; and CD1 mice also had a greater loss of renal perfusion and kidney volume than B6 mice ( P < 0.05). CD1 mice developed substantial interstitial fibrosis and decreased peritubular capillary (PTC) density by day 14 while B6 mice showed only mild renal scarring and almost normal PTC. Our results show that after IRI, CD1 mice develop more inflammation, hypertension, and later mesangial matrix expansion than B6 mice do. Subsequently, CD1 animals suffer from CKD due to impaired renal perfusion and pronounced permanent loss of peritubular capillaries.

Diffusion Weighted Imaging and T2 Mapping Detect Inflammatory Response in the Renal Tissue during Ischemia Induced Acute Kidney Injury in Different Mouse Strains and Predict Renal Outcome

“…In a previous study, tubular epithelial cell proliferation early after renal IRI was present in B6 and absent in CD1. In addition, CD1-mice had increased rarefication of peritubular capillaries following IRI, which was associated with development of progressive renal fibrosis [9]. In this study, we showed that ADC and T2 values might be useful as predictive marker for progression to CKD.…”

“…Tissue water content (such as edema) and infiltration of inflammatory cells (leading to a reduced diffusivity) are hallmarks of IRI and can be quantified by functional MRI. It has been demonstrated in a previous study that CD1 mice have an increased susceptibility to renal IRI compared to B6 mice [9]. In this study, we evaluated whether DWI and T2 mapping on functional MRI could detect morphological differences reflecting this different susceptibility.…”

“…C57BL/6 (B6) mice are a commonly used mouse strain for IRI-induced AKI studies and background for many genetic knockout models in renal IRI [6,7]. However, strainspecific differences in the susceptibility to renal IRI have been described [8,9]. A recent study used functional MRI in CD1 mice and found that they exhibit pronounced renal perfusion impairment following IRI compared to B6 [9].…”

“…However, strainspecific differences in the susceptibility to renal IRI have been described [8,9]. A recent study used functional MRI in CD1 mice and found that they exhibit pronounced renal perfusion impairment following IRI compared to B6 [9]. In addition, CD1 mice had blood pressure elevation and glomerular injury following partial nephrectomies [10].…”

Mas Receptor Blockade Promotes Renal Vascular Response to Ang II after Partial Kidney Ischemia/Reperfusion in a Two-Kidney-One-Clip Hypertensive Rats Model

“…e renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure and fluid and electrolyte homeostasis [9,10]. Hypertension and RAS are influenced by IR [11][12][13]. e RAS consists of two counterregulatory axes, divided into the conventional axis and includes angiotensin II (Ang II), angiotensin-converting enzyme (ACE), Ang II type 1 receptor (AT 1 R), and the nonconventional axis composed of Ang1-7 ACE2, Ang II type 2 receptor (AT 2 R), and Mas receptor (MasR) [13].…”