ABSTRACT
Mannan-binding lectin (MBL) initiates the lectin pathway of complement and has been linked to albuminuria and mortality in diabetes. We hypothesize that MBL-associated serine protease 2 (MASP-2) deficiency will protect against diabetes-induced kidney damage. Male C57BL/6J MASP-2 knockout (Masp2-/-) mice and wildtype (WT) mice were divided into a diabetic group and a non-diabetic group. Renal hypertrophy, albumin excretion, mesangial area and specific mRNA expressions in the renal cortex were measured after 8 and 12 weeks of diabetes. By two-way ANOVA it was tested if MASP-2 modulated the renal effects of diabetes, that is interaction. After 12 weeks of diabetes Masp2-/- diabetic mice had a smaller mesangium at 21.1% of the glomerular area (95% CI 19.7, 22.6) compared with WT diabetic mice, 25.2% (23.2, 27.2), p(interaction) = 0.001. After 8 weeks of diabetes, plasma cystatin C was 261.5 ng/mL (229.6, 297.8) in the WT diabetic group compared to 459.9 ng/mL (385.7, 548.3) in non-diabetic WT mice, p < 0.001. By contrast, no difference in plasma cystatin C levels was found between the Masp2-/- diabetic mice, 288.2 ng/mL (260.6, 318.6) and Masp2-/- non-diabetic mice, 293.5 ng/mL (221.0, 389.7), p = 0.86 and p(interaction) = 0.001. We demonstrated a protective effect of MASP-2 deficiency on mesangial hypertrophy after 12 weeks of diabetes and an effect on plasma cystatin C level. MASP-2 deficiency did, however, fail to protect against diabetic-induced alterations of kidney weight, albuminuria and renal mRNA expression of fibrotic- and oxidative stress markers.
Subject(s)
Diabetes Mellitus, Type 1 , Diabetic Nephropathies , Mannose-Binding Protein-Associated Serine Proteases , Mice, Inbred C57BL , Mice, Knockout , Animals , Mannose-Binding Protein-Associated Serine Proteases/metabolism , Mannose-Binding Protein-Associated Serine Proteases/genetics , Mannose-Binding Protein-Associated Serine Proteases/deficiency , Diabetic Nephropathies/etiology , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Mice , Male , Diabetes Mellitus, Type 1/complications , Disease Models, Animal , Disease Progression , Cystatin C/blood , Diabetes Mellitus, Experimental/complications , AlbuminuriaABSTRACT
In the introduction, we briefly recall old but classic evidence that there is no tolerance to paternal alloantigens in a first pregnancy. Therefore, we performed small- and large-scale microarrays in CBA × DBA/2 and CBA × BALB/c combinations, recently described as a murine model for preeclampsia. Our results are in line with other data suggesting a very early deregulation of local immune vascular events rather than a break of immune tolerance. Other data presented at the Tioman 2010 Preeclampsia Workshop supporting this hypothesis are briefly summarised, as well as indications and caveats from a recent human microarray on implantation failure and recurrent pregnancy loss.
Subject(s)
Gene Expression Regulation/immunology , Immune Tolerance , Pre-Eclampsia/metabolism , Animals , Disease Models, Animal , Female , Gene Expression Profiling/methods , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Inbred CBA , Mice, Inbred DBA , Oligonucleotide Array Sequence Analysis/methods , Pre-Eclampsia/genetics , Pre-Eclampsia/immunology , PregnancyABSTRACT
This paper reports a summary of our comparative analysis of the uterine expression of interleukin-23 (IL-23), IL-27 and TWEAK in the CBA/J femalexDBA/2 male mouse mating combination, a model of immune-mediated early pregnancy loss. Compared with the MHC-identical CBA/JxBALB/c mating combination, which yields successful pregnancies, immunohistochemistry and qPCR in uterine tissue showed an immediate post-mating IL-27 hyper-expression after mating with DBA/2 males. Intra-uterine TWEAK expression was present in females mated with DBA/2 or Balb/c males from days 0.5 to 4.5 post-coitum (pc), peaking on day 0.5 pc together with uterine TNFalpha. In uteri of DBA/2 mated mice, TWEAK declined to almost undetectable levels on days 6.5-9.5 pc, a steeper drop than in BALB/c mated mice where TWEAK remained detectable. In both mating combinations, neutralisation of TWEAK by antibodies increased resorption rates, but surprisingly, so did IL-27 neutralisation. The complement regulator mannan binding lectin-A (MBL-A), but not MBL-C, was present on day 4.5 pc especially after mating with DBA/2 males. High levels of MBL are present in the uterine luminal fluid of sterile women, and possible functions for TWEAK and MBL in human implantation are indicated by their protein and mRNA expression in uterine biopsies from infertile and fertile individuals. Consistent with the results in mice, increased MBL expression is linked with pregnancy failure. Serum and uterine VEGF and VEGF receptor levels are also different between fertile and sterile patients. The implications of these findings for utilising the CBA/JxDBA/2 mating combination as an early onset model of preeclampsia are discussed.
