The global prevalence of chronic kidney disease (CKD) has risen at an accelerating rate, increasing the global healthcare burden for long-term and chronic care costs. Multiple risk factors including hypertension, diabetes, and dyslipidemia synergistically induce the progression of CKD. Chief among these factors are dyslipidemia and obesity; increased free fatty acid uptake due to excess consumption of lipid-rich diets has been shown to promote intra-renal lipid accumulation in several in vivo models and in patients in various stages of CKD. Furthermore, patients with renal disease are also at a substantially higher risk for atherosclerotic cardiovascular disease (CVD). In the general population, as well as in patients with renal disease, circulating low-density lipoprotein cholesterol (LDLc) is a well-established driver of atherosclerotic lesion development and CVD progression. In 2003, the proprotein convertase subtilisin/kexin type-9 (PCSK9) was identified as the third locus of familial hypercholesterolemia and was further characterized for its ability to enhance the degradation of the low-density lipoprotein receptor (LDLR). Since this seminal discovery, the development of monoclonal antibodies targeted against PCSK9 demonstrated a significant reduction in LDLc and subsequent CVD risk, establishing the remarkable ‘bench to bedside’ transition. However, the inherent role of PCSK9 in regulating lipid homeostasis remained unknown in different pathological conditions. In the first chapter of my thesis, I demonstrate that PCSK9 regulates the LDLR as a feedback mechanism to protect against non-alcoholic steatohepatitis (NASH) progression induced by a high-fat diet (HFD) challenge.
Since its seminal discovery, PCSK9 was also characterized to modulate a wide variety of receptors known to play a crucial role in lipid metabolism including the cluster of differentiation 36 (CD36), the very low-density lipoprotein receptor (VLDLR), and the apolipoprotein E receptor 2 (ApoER2). Previously, we have demonstrated that the absence of PCSK9 promotes diet-induced non-alcoholic steatohepatitis and liver injury through increased surface expression of CD36. Given that these same receptors are well-expressed on renal epithelia, the second chapter of my thesis demonstrates that PCSK9 is also able to modulate renal lipid metabolism by attenuating tubular lipid accumulation and subsequent renal injury.
Furthermore, when PCSK9 was first characterized by Seidah and colleagues in 2003, in situ hybridization of murine PCSK9 demonstrated that it was primarily expressed in the liver, but also well-expressed in the kidney cortex, cerebellum, and small intestines. Despite its expression in a wide range of tissues, the secretion of PCSK9 was exclusive to the liver, thus, questioning what the intracellular role of PCSK9 may be. Hence, my last chapter of my masters studies lies in establishing the role of intracellular PCSK9 expression in a cellular process known as endoplasmic reticulum (ER) stress in the kidney. ER stress is a phenomena which primarily occurs due to increased accumulation of misfolded polypeptides, and has been implicated in numerous metabolic diseases including hepatic steatosis, CKD, and neurodegenerative pathologies. Previously, we have demonstrated that overexpressing wild-type and variants of PCSK9 in a Pcsk9-/- mouse does not induce the activation of the unfolded protein response (UPR) and attenuates hepatic ER stress. Using a well-established CKD model, I show that Pcsk9-/- mice exhibit increased renal ER stress and injury relative to wild-type controls. Overall, my findings demonstrate for the first time that both extracellular and intracellular PCSK9 has the ability to modulate renal injury using two distinct mechanism to protect against CKD progression. / Thesis / Master of Health Sciences (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/25447 |
| Date | January 2020 |
| Creators | Byun, Jae Hyun |
| Contributors | Austin, Richard, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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