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Title: Triglyceride-rich lipoproteins influence monocyte and macrophage homeostasis and exacerbate experimental kidney injury
Author: Saja, Maha Fahad
ISNI:       0000 0004 6348 1147
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Hypertriglyceridemia and its associated increase in triglyceride-rich lipoproteins (TGRLs) is a great threat to today’s modern society. Sedentary life style and western type diet subject our bodies to repetitive influx of TGRLs following each meal which is being increasingly recognised as a risk factor for coronary artery disease (CAD). Moreover, a hyper-TGRL state complicates the course of various immunological and non-immunological conditions contributing to both morbidity and mortality. How TGRLs mediate their harmful effects is unclear. In view of their ideal location, monocytes (MOs) are at the front line against fluctuating levels of TGRLs, yet the influence of such an environment on their behaviour remain obscure. With the growing recognition of MO heterogeneity, the impact of this diversity on MO functions deserves more attention. In the mouse, two MO subsets are recognized; Gr1-high or “inflammatory” MOs, known to populate inflamed tissue giving rise to macrophages (MØs) and the Gr1-low or “patrolling” MOs, shown to crawl along the endothelial surface under steady-state conditions and rarely extravasate. To explore whether changes in TGRLs could alter MO behaviour, I used a compound, P-407, that induces a dose-dependent increase in TGRLs in C57BL/6 (B6) mice. The increase in plasma TGRLs led to a sharp drop in blood Gr1-low MOs subsets while levels of Gr1-high MOs remained unchanged. The drop in Gr1-low MOs was associated with accumulation of CD68+ MØs in the liver, heart, and kidney. In the absence of an inflammatory insult, CD68+ MØs did not trigger kidney injury. However, with an inflammatory insult (accelerated nephrotoxic nephritis), the kidneys of P-407 injected mice exhibited more renal damage. Collectively my findings demonstrate that an environment loaded with TGRLs influences the steady state behaviour of MOs and MØs, and primes the kidney for injury during inflammation.
Supervisor: Botto, Marina ; Pickering, Matthew Sponsor: Government of Saudi Arabia ; Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral