Ismail Laher

Epidemiological studies demonstrate an association between obstructive sleep apnea (OSA) and accelerated loss of kidney function. OSA is characterized by repetitive episodes of intermittent hypoxia (IH) during sleep, which provokes systemic and renal oxidative stress and inflammation. Here we hypothesized that IH induces structural and functional renal injury by increasing glomerular growth factors, increasing oxidative stress and inflammation, and that α-lipoic acid (LA), an antioxidant, attenuates this injury. To address this hypothesis, the ability of LA to mitigate the structural and functional aspects of renal injury secondary to IH was examined.Ten 8-week old wild-type male CB57BL/6 mice were randomly assigned to receive either IH or intermittent air (IA) for 60 days. The first study involved histological measurements of glomerular area and mesangial matrix expansion (MME), where glomerular growth factors were quantified by immunohistochemistry. Renal cellular apoptosis was investigated by measuring apoptotic proteins in kidney cortex. Finally, measurements of renal function were made by measuring serum creatinine and 24-hour urinary albumin. For the second study, 20 mice were randomized to receive either IH or IA, with regular diet (RD) or 0.2% w/w LA-enriched diet. After 60 days, samples of urine and plasma were collected. Markers for oxidative stress, inflammation, apoptosis, and tubular injury in kidney cortex were quantified. Glomerular area and MME were measured as well.Compared to controls, IH-exposed mice had increased glomerular areas and MME, accompanied by increases in glomerular growth factors and cellular apoptosis markers. IH-exposed mice had increases in albuminuria but not in serum creatinine. The second study demonstrated reduced urinary albumin excretion in the IH-LA group compared to IH-RD. Histological assessment showed significant increases in glomerular area of IH-RD compared to IH-LA. Treatment with LA also normalized systemic and renal oxidative stress and inflammation, and attenuated renal cellular apoptosis and tubular injury secondary to IH.These findings indicate for the first time that IH causes structural and functional kidney injury and increases renal cellular apoptosis, and this injury was attenuated by the antioxidant effect of LA. Treatment with LA may be a potentially promising therapy to reduce renal dysfunction in patients with OSA.

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Obstructive sleep apnea (OSA) is a chronic condition characterized by recurring upper airway collapse during sleep, leading to chronic intermittent hypoxia (CIH) that can evoke oxidative stress and inflammation leading to cardiovascular disease (CVD). Current treatments for OSA are relatively ineffective in preventing CVD. Moreover, the effects of gestational OSA on the health of the offspring are unknown. We hypothesized that 1) antioxidant treatment can improve vascular outcomes in mice exposed to CIH and that 2) gestational intermittent hypoxia (GIH) can adversely impact fetoplacental outcomes and lead to cardiometabolic disease in the adult offspring. The first chapter of this thesis examines the effects of CIH on vascular function, oxidative stress and inflammatory markers in CB57BL/6 male mice with or without treatment with the dietary antioxidant, alpha lipoic acid (ALA). CIH impaired aortic relaxation and basal nitric oxide (NO) production. Furthermore, CIH increased systemic oxidative stress, inflammation and proinflammatory gene expression in the aorta. Treatment with ALA improved endothelial function and reduced oxidative stress and inflammation.In the second chapter, the impact of 14.5 days of GIH on vascular function of pregnant mice is reported. The following were evaluated: uterine artery function, plasma oxidative stress and inflammatory markers, spiral artery remodeling, placental morphology, hypoxia, oxidative stress, and fetal weights. GIH increased placental weights and decreased fetal weights, impaired uterine artery function, increased systemic oxidative stress and inflammation, increased placental hypoxia, and oxidative stress with no effect on spiral artery remodeling. In the third chapter, aortic endothelial and perivascular adipose tissue (PVAT) function were evaluated in sixteen-week-old offspring of dams exposed to GIH only in utero. GIH male offspring had increased body weights and developed metabolic syndrome. Furthermore, aortic relaxation was impaired in offspring with a loss of PVAT anti-contractile effects, which was facilitated by adiponectin. Levels of adiponectin were lower in the PVAT and in plasma. Pyrosequencing of adiponectin promoter in PVAT indicated increased DNA methylation in male GIH offspring. These data suggest that treatment of OSA patients with ALA could be a strategy to improve cardiovascular outcomes. Furthermore, maternal OSA may lead to adverse metabolic and vascular outcomes during adulthood.

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Background: The high mortality and morbidity rates associated with diabetes are mainly attributed to its cardiovascular complications. It remains questionable whether diabetes has a general deleterious effect on the vasculature, or if different arteries exhibit differential vulnerability to the diabetic milieu. This thesis compared the functional adaptation of three arteries: the aorta, carotid and femoral arteries, to the diabetic milieu present in db/db mice, and elucidated the mechanisms underlying the arteries' differential adaptation. Additionally, the functional and molecular alterations in the aorta and femoral artery in response to moderate-intensity exercise training were compared. Methods: Vasodilatory and contractile responses were examined in isolated aortae, carotid and femoral arteries from db/db and control mice to assess the endothelium and vascular smooth muscles' functions. Additionally, the protein expressions of endothelial nitric oxide synthase (eNOS), Akt, cyclooxygenase and superoxide dismutase (SOD) isoforms were examined. In parallel, plasma markers of glycemia, oxidative stress, inflammation, and dyslipidemia were measured. Thereafter, a correlation analysis was performed to estimate the strength of association between plasma variables and vascular responses. Results: The aortae of db/db mice exhibited a progressive impairment in endothelial and vascular smooth muscle functions. The carotid artery was the most resilient and maintained unaltered functional responses in db/db mice, likely because the carotid artery, in contrast to the aorta, relaxes in response to superoxide anion or peroxynitrite. The femoral arteries of db/db mice showed reduced endothelium-dependent hyperpolarizing factor-mediated vasodilatation and attenuated contractile responses, probably due to the lack of expression of extracellular SOD in the femoral artery. The benefits of exercise training were confined to nitric oxide-mediated vasodilatation in the aortae and femoral arteries of db/db mice, and were associated with increased eNOS/Akt and SOD expressions and reduced cardiovascular risk factors.Conclusions: Substantial heterogeneity exists between the aorta, carotid and femoral arteries both at functional (signalling pathways) and molecular levels (protein expression) under physiological and diabetic conditions. Understanding regional differences in vasomotor control, coupled with advanced drug delivery systems will open new venues for developing therapies that target specific vascular beds with minimal systemic side effects.

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No abstract available.