Amelioration of nephropathy with apoA-1 mimetic peptide in apoE-deficient mice.
BACKGROUND
There is mounting evidence that dyslipidaemia may contribute to development and progression of renal disease. For instance, hyperlipidaemia in apolipoprotein E-deficient (apoE(-/-)) mice is associated with glomerular inflammation, mesangial expansion and foam cell formation. ApoA-1 mimetic peptides are potent antioxidant and anti-inflammatory compounds which are highly effective in ameliorating atherosclerosis and inflammation in experimental animals. Given the central role of oxidative stress and inflammation in progression of renal disease, we hypothesized that apoA-1 mimetic peptide, D-4F, may attenuate renal lesions in apoE(-/-) mice.


METHODS
Twenty-five-month-old female apoE(-/-) mice were treated with D-4F (300 µg/mL in drinking water) or placebo for 6 weeks. Kidneys were harvested and examined for histological and biochemical characteristics.


RESULTS
Compared with the control mice, apoE(-/-) mice showed significant proteinuria, tubulo-interstitial inflammation, mesangial expansion, foam cell formation and up-regulation of oxidative [NAD(P)H oxidase subunits] and inflammatory [NF-κB, MCP-1, PAI-1 and COX-2] pathways. D-4F administration lowered proteinuria, improved renal histology and reversed up-regulation of inflammatory and oxidative pathways with only minimal changes in plasma lipid levels.


CONCLUSIONS
The apoE(-/-) mice develop proteinuria and glomerular and tubulo-interstitial injury which are associated with up-regulation of oxidative and inflammatory mediators in the kidney and are ameliorated by the administration of apoA-1 mimetic peptide. These observations point to the role of oxidative stress and inflammation in the pathogenesis of renal disease in hyperlipidaemic animals and perhaps humans.
Vaziri
Nosratola D
ND
Division of Nephrology and Hypertension, University of California, Irvine, CA, USA. ndvaziri@uci.edu
Kim
Hyun Ju
HJ
Moradi
Hamid
H
Farmand
Farbod
F
Navab
Kaveh
K
Navab
Mohamad
M
Hama
Susan
S
Fogelman
Alan M
AM
Quiroz
Yasmir
Y
Rodriguez-Iturbe
Bernardo
B
D000818:Animals; D016632:Apolipoprotein A-I / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000172:deficiency*; D018932:Chemokine CCL2 / Q000096:biosynthesis; D005260:Female; D006949:Hyperlipidemias / Q000150:complications*; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008075:Lipoproteins, HDL / Q000502:physiology; D008077:Lipoproteins, LDL / Q000502:physiology; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism; D058258:Serpin E2 / Q000096:biosynthesis
D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C465468:D-4F peptide; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D019255:NADPH Oxidases