Renal protective effects of induction of haem oxygenase‐1 combined with increased adiponectin on the glomerular vascular endothelial growth factor–nitric oxide axis in obese rats

Abstract

What is the central question of this study? This study aimed to investigate whether induction of haem oxygenase-1 (HO-1) can protect the kidneys of obese rats by regulating the glomerular vascular endothelial growth factor-nitric oxide (VEGF-NO) axis by increasing the adiponectin concentrations. What is the main finding and its importance? Induction of HO-1 reduces the degree of microalbuminuria and has renal protective effects by improving endothelial function and regulating the uncoupled glomerular VEGF-NO axis in diet-induced obese rats. The mechanism may be related to increased activation of the HO-1-adiponectin axis. The glomerular vascular endothelial growth factor-nitric oxide (VEGF-NO) axis plays a critical role in maintenance of normal kidney function in obesity. Induction of haem oxygenase-1 (HO-1) may result in a parallel increase in adiponectin secretion. The aim of this study was to investigate whether induction of HO-1 could protect the kidneys of obese rats by regulating the glomerular VEGF-NO axis by increasing adiponectin levels. Rats received high-fat diets and were injected with either cobalt protoporphyrin to induce HO-1 or stannous protoporphyrin to inhibit HO-1. Blood and urine samples were collected. Endothelial function was determined by measuring the endothelium-dependent vasodilatation of the aorta. Renal tissues were collected for CD34 immunohistochemistry. The glomerular VEGF-NO axis and the AMP kinase-phosphoinositide 3-kinase (PI3K)/Akt-endothelial nitric oxide synthase pathway were measured. Induction of HO-1 by cobalt protoporphyrin decreased microalbuminuria, plasma free fatty acids, serum high-sensitivity C-reactive protein and malondialdehyde levels and increased serum adiponectin levels compared with the untreated obese rats. Severe impairment of endothelium-dependent vasodilatation was observed in the obese rats, which was improved to some extent by HO-1 induction. Induction of HO-1 reduced glomerular CD34 expression and production of reactive oxygen species in obese rats. Obese rats showed increased glomerular VEGF expression and reduced NO levels. This uncoupling of the glomerular VEGF-NO axis was improved to some extent by induction of HO-1, with enhancement of p-AMP kinase, p-Akt and phospho-endothelial nitric oxide synthase in obese rats. These results indicate that induction of HO-1 with cobalt protoporphyrin reduces the degree of microalbuminuria and has renal protective effects by improving endothelial dysfunction and regulating the glomerular VEGF-NO axis in diet-induced obese rats by increasing adiponectin levels.

Upregulation of heme oxygenase 1 (HO-1) attenuates kidney damage, oxidative stress and inflammatory reaction during renal ischemia/reperfusion injury

“…Also, chronic induction of HO-1 exhibited protective effects in a rat model of hepatic ischemic injury (Fang et al 2011) and controlled renal hemodynamics and renal excretory function in ischemic kidney diseases (Ferenbach et al 2010). Additionally, HO-1 possesses antioxidant and anti-inflammatory properties that are essential for NO preservation (Liu et al 2015).…”

Irisin Regulates Heme Oxygenase-1/Adiponectin Axis in Perivascular Adipose Tissue and Improves Endothelial Dysfunction in Diet-Induced Obese Mice

“…Mice in the NC group were fed a normal chow diet and mice in the other two groups were fed a HFD (493 kcal 100 g –1 ) [18]. Mice in the irisin group were given recombinant irisin (0.5 μg/g/day; Phoenix Pharmaceuticals, Inc., Burlingame, CA, USA) by intraperitoneal injection daily [12, 14]. The other two groups were given physiological saline as control.…”

“…HO-1 is the major enzyme of heme metabolism decomposition and can be induced by various oxidative insults. Upregulation of HO-1 may induce an increase in adiponectin secretion by remodeling adipose tissue, which prevents endothelial dysfunction by its anti-oxidative and anti-inflammatory effects [14-16]. Previously, we observed that irisin improves the PVAT dysfunction from the thoracic aorta in died-induced obese mice through upregulation of the HO-1/adiponectin axis and browning of PVAT [17].…”

“…The heme oxygenase-1 (HO-1)/adiponectin axis has recently demonstrated to have beneficial effects on cardiovascular disease [13, 14]. HO-1 is the major enzyme of heme metabolism decomposition and can be induced by various oxidative insults.…”

Characterisation of the relationship between Heme-oxygenase-1 and adiponectin

“…Like others [217,237,241,242,272,279,306], we found that CoPP administration prevented weight gain in HFD-induced obese mice. However, this effect was not prevented by co-treatment with SnMP, implying HO-1-independence, whereas the effect was abolished or reduced by SnMP in studies of genetically (ob/ob mice) [217,237] or HFD-induced [306] obese mice or rats [287]. The reasons for the differential sensitivity to SnMP is unclear.…”