Journal of Lipid Research, Vol 32, 1675-1687, Copyright © 1991 by Lipid Research, Inc.
Dyslipoproteinemia in an inbred rat strain with spontaneous chronic progressive nephrotic syndrome
P Tarugi, S Nicolini, L Albertazzi, S Calandra, P Salvati, C Ferti and C Patrono
Istituto di Patologia Generale, Universita di Modena, Italy.
Rats of the Milan Normotensive Strain (MNS) develop a dyslipoproteinemia
that is associated with a spontaneous, age-dependent and slowly progressive
nephropathy characterized by proteinuria and hypoalbuminemia (nephrotic
syndrome). We assumed that the MNS strain might be a suitable model for
studying the features of nephrotic dyslipoproteinemia and its relationship
with proteinuria, hypoalbuminemia, and hepatic apolipoprotein production.
Plasma lipoproteins were investigated in MNS rats at various ages (4-48
weeks) and in another rat strain (Milan Hypertensive Strain, MHS),
genetically related to MNS but free of nephropathy, that was used as
control. In MNS rats, abnormal proteinuria was detectable at 20 weeks and
increased 2-fold up to 34 weeks with no reduction of plasma albumin
(compensated stage). During this stage we found increased levels of plasma
cholesterol (+ 34%), high density lipoprotein-1 (HDL1) (+ 73%), and HDL2 (+
31%) that were positively correlated with proteinuria but not with plasma
albumin. The later stage (34-48 weeks) (nephrotic stage) was characterized
by a further increase of proteinuria, moderate hypoalbuminemia (- 25%), a
2-fold increase of plasma cholesterol, triacylglycerols, low density
lipoprotein (LDL), and HDL1, and a 1.2- fold increase of HDL2. In this
stage the levels of LDL, HDL1, and HDL2 were positively correlated with
proteinuria, and negatively correlated with plasma albumin. The most
striking change in apolipoproteins was a progressive increase of the
relative content of apoA-I in HDL (in 48- week-old MNS rats the A-I/E ratio
was 3-fold that found in MHS rats) that was associated with a similar
increase of plasma apoA-I. None of these lipoprotein changes were observed
in age-matched MHS rats. At the end of the compensated stage, the hepatic
levels of A-I, B, A-II, and albumin mRNA were 5.3-, 3.5-, 1.3-, and
2.0-fold, respectively, those found in age-matched MHS rats. During the
nephrotic stage, albumin mRNA continued to increase, whereas A-I, B, and
A-II mRNAs decreased toward the levels found in age-matched MHS rats. Thus,
nephrotic dyslipoproteinemia in MNS rats starts to develop in the
compensated stage before the onset of hypoalbuminemia, is characterized by
an early elevation of HDL1 + HDL2, and is associated with an increased
content of hepatic mRNAs of some apolipoproteins, especially apoA-I. The
slow progression of nephrotic syndrome with the long-standing proteinuria
and no reduction in plasma albumin renders the MNS strain the most suitable
animal model for the study of the effect of proteinuria on plasma
lipoprotein metabolism.
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