A Protective Role for Kidney Apolipoprotein E

Abstract

Mesangial expansion is a key feature in the pathogenesis of numerous renal diseases involving the glomerulus. Studies indicate that mutations in apolipoprotein E (apoE) might independently contribute to kidney dysfunction. Although the role of apoE as an atheroprotective molecule is well established, its role in kidney is unclear. In this study, we sought to explore whether apoE has a protective function in kidney. Northern blotting and reverse transcriptase-polymerase chain reaction showed apoE expression in kidney, and mesangial cell is a major source of apoE in kidney. In the kidneys of 14 -16-month-old apoE-null mice, hematoxylin-eosin (HE) staining revealed increased mesangial cell proliferation and matrix formation compared with wild type mice or apoB-overexpressing mice, which have elevated plasma cholesterol and triglycerides. These data suggest that lack of apoE, rather than hyperlipidemia, contributes to increased mesangial expansion. We isolated mesangial cells from mouse kidney and determined the effect of apoE on cell growth. ApoE (E3, 10 g/ml) completely inhibited serum, platelet-derived growth factor (10 ng/ml), as well as low density lipoprotein-induced mesangial cell proliferation. Among the three isoforms, E3 was found to be most effective in inhibiting mesangial cell proliferation. ApoE did not show any cytotoxic effect, and moreover, inhibited mesangial cell apoptosis induced by oxidized low density lipoprotein. These data suggest that apoE regulates growth as well as survival of mesangial cells. We previously showed that apoE induces matrix heparan sulfate proteoglycan (HSPG) in vascular cells, which has an antiproliferative effect. Similarly, apoE induced the mesangial matrix HSPG. Perlecan is the major HSPG of mesangial matrix and subendothelial space, and consistent with this, blockade of perlecan reversed the antiproliferative effect of apoE. Immunohistochemistry revealed reduced staining of perlecan in kidney from apoE-null mice. Because the loss of anionic HSPG in the basement membrane and mesangial matrix is associated with disruption of filtration barrier, these data suggest a novel role for kidney apoE in preserving the filtration barrier. In summary, apoE has a protective function in kidney as an autocrine regulator of mesangial expansion and kidney function.

Apolipoprotein E Regulates Primary Cultured Human Mesangial Cell Proliferation

“…A recent study showed that apo E acts as autocrine regulator of mesangial and glomerular function [17]. Although the mechanism is unclear, our study, that used primary cultured normal human mesangial cells in FCS-free medium, a condition different from theirs, does provide further evidence in the fact that apo E, without causing NHMC apoptosis and interfering cell cycles, increased or decreased NHMC proliferation, and at different days in culture.…”

“…The deposition of apo B and apo E in glomeruli accelerates the progression of mesangial lesions [9]. However, this result agreed with Chen’s recent observations in apo E null mice in which there was significant mesangial cell proliferation in glomeruli [17], implying that in normal wild mice apo E directly or indirectly inhibits mesangial cell proliferation. This inhibition was not caused by apoptosis or toxic effect of apo E. Our studies showed that apo E caused no apoptosis, nor did it affect cell cycles.…”

“…apo E at high concentrations (5 and 10 µg/ml) increased NHMC proliferation in the first 24 h but inhibited it after 48 h. Although the reason is unknown, this phenomenon suggests that the apo E effect on NHMC proliferation is not only inhibitory but also stimulative. Because apo E has inhibitory effect on mesangial cell apoptosis [17], it might regulate NHMC proliferation in different cell conditions, such as cell growth rate or apo E receptor changes in number or affinity. The mechanism of this phenomenon is likely to be applied to explain the difference in contrary effects of apo E, i.e.…”

Divergent Effects of Peroxisome Proliferator-activated Receptor γ Agonists and Tumor Necrosis Factor α on Adipocyte ApoE Expression

“…For example, disordered apoE function/expression has a well established role in the pathophysiology of important human diseases such as atherosclerosis and dementia (1)(2)(3)(4)(5)(6). ApoE has also been implicated in regulating the expansion of the renal mesangial matrix, in regulating the differentiated function of steroidogenic tissues, and protecting cells from oxidant stress (7)(8)(9). In line with its diverse roles in normal mammalian physiology, apoE is expressed in multiple cell types, including vessel wall macrophages and cells of the central nervous system, in steroidogenic tissue, and in the kidney (1)(2)(3)(4)(5)(6)(7)(8)(9).…”

“…ApoE has also been implicated in regulating the expansion of the renal mesangial matrix, in regulating the differentiated function of steroidogenic tissues, and protecting cells from oxidant stress (7)(8)(9). In line with its diverse roles in normal mammalian physiology, apoE is expressed in multiple cell types, including vessel wall macrophages and cells of the central nervous system, in steroidogenic tissue, and in the kidney (1)(2)(3)(4)(5)(6)(7)(8)(9). As a surface component of lipoproteins, apoE is involved in regulating organismal lipoprotein metabolism (1)(2)(3)(4).…”