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Human apolipoprotein E (ApoE) is a glycoprotein that serves as a ligand for the receptor-mediated uptake of lipoprotein via the low-density lipoprotein receptor. It is associated with chylomicrons, very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL). Among the different isoforms of ApoE, ApoE3 is the most common and is anti-atherogenic. However, individuals with ApoE4 are associated with increased cholesterol levels and VLDL to HDL ratio respectively.
Furthermore, ApoE4 is a major genetic risk factor for developing sporadic Alzheimer's disease (AD) and its pathogenesis is linked to intracellular lipid accumulation in astrocytes. Moreover, cognitive decline in AD appears to be expedited by chronic kidney disease (CKD). Given the kidneys’ reliance on lipids as their primary energy source, current research is unable to draw a consensus on the impact of ApoE4 on lipid accumulation and disrupted lipid metabolism in the kidney. We hypothesized that ApoE4 may disrupt lipid metabolism, leading to lipid accumulation, and potentially contributing to the progression of CKD.
To investigate, wild-type (WT) C57BL/6J and humanized ApoE3 (hApoE3+/+), ApoE4 (hApoE4+/+) and ApoE knockout (ApoE-/-) mice were used to mimic sporadic AD with dyslipidaemia. Mice were sacrificed at the age of 10 and 16 months and the kidney and liver were collected for histological analysis.
ApoE KO-10mo mice exhibited an increased number of glomeruli with mild mesangial expansion. Also, the glomerular basement membrane (GBM) exhibited thickening and enlargement in glomerular area in comparison to their age matched ApoE WT controls. In ApoE KO-16mo mice, there is evidence of further exacerbation of glomerular morphological alterations, characterised by dilated capillaries, hyaline deposits and increased size. Interestingly, minimal mesangial expansion was noted between ApoE WT-10mo and -16mo (Fig. 1 and 2). Collectively, these findings suggest a progressive deterioration in renal function in ApoE KO mice compared to ApoE WT counterparts over time.
In hApoE4+/+-10mo, there is an increased in glomerular number and severity of mesangial expansion. Also, the glomerular area is increased with thickening of the GBM when compared to their age-matched controls. Whilst these morphological abnormalities are worsened in 16-mo samples of both groups, hApoE4+/+-16mo exhibits the most severe morphological alterations and prominent hyaline deposition in the glomerulus (Fig. 3 and 4). This suggests an accelerated progression of CKD in hApoE4+/+ mice.
Moreover, lipid accumulation, inflammation and fibrosis are observed in a similar manner amongst the groups. ApoE KO and hApoE4+/+ mice exhibit heightened severity in these aspects compared to their age-matched controls. Focal inflammation is also observed in ApoE KO-16mo and all age groups of hApoE4+/+ (Fig. 5 and 6).
The liver morphology in all four groups is similar. This suggests that liver pathophysiology is not a contributing factor to the observed pathological changes in the kidney (Fig. 7).
To conclude, both ApoE KO and hApoE4+/+ mice demonstrated altered renal morphology with lipid accumulation – signifying kidney injury. Further studies on the mechanism of lipid accumulation leading to cell dysfunction are required to establish a full understanding of the contribution of ApoE4 to CKD.