Universiẗat, Diss.--Hannover, 1999.

Thesis (doctoral)--University of Jyväskylä, 1983. / At head of title: The Department of Clinical Sciences, University of Tampere, the Department of Cell Biology, University of Jyväskylä. Includes bibliographical references.

Thesis (doctoral)--University of Jyväskylä, 1983. / At head of title: The Department of Clinical Sciences, University of Tampere, the Department of Cell Biology, University of Jyväskylä. Includes bibliographical references.

Celiac disease, an inflammatory disease of small bowel caused by sensitivity to dietary gluten and related protein, affects approximately 0.5-1% of the population in the Western world. Extra-intestinal symptoms and associated diseases are increasingly recognized including diabetes mellitus type 1, thyroid disease, dermatitis herpetiformis and ataxia. There have also been a number of reports of various types of renal involvement in patients with celiac disease including diabetes nephropathy, IgA nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis, nephrotic syndrome related to malabsorption, oxalate nephropathy, and associations of celiac disease with chronic kidney disease and end-stage kidney disease. This review aims to present the current literature on possible pathologic mechanisms underlying renal disease in patients with celiac disease.

Conjugated linoleic acid (CLA) has been shown to reduce inflammation via Peroxisome Proliferator-Activated Receptor (PPAR)-γ in inflammatory disorders such as Crohn's Disease and Inflammatory Bowel Disease. We sought to determine whether CLA isomers would reduce inflammation via PPAR-γ in cultured mesangial cells, and in murine models of anti-glomerular basement membrane (anti-GBM) glomerulonephritis and Systemic Lupus Erythematosus (SLE). SV40-transformed mouse mesangial cells (MES13) were cultured with pure CLA isomers (c9,t11 or t10,c12-CLA or a 50:50 mixture prior to immune stimulation with lipopolysaccharide and interferon-γ. Next, cultured mesangial cells were transfected with small interfering RNA (siRNA) targeting PPAR-γ and treated with CLA isomers prior to immune stimulation. ELISA, qPCR, Western blot, and Griess reaction were performed to measure cytokine production, mRNA expression, induced nitric oxide synthase (iNOS) and nitrite production, respectively. Next, myeloid-specific (LysM creR2+) PPAR-γ knockout mice were treated with CLA prior to the induction of anti-GBM glomerulonephritis and evaluated for disease. Finally, NZM2410/J mice (a natural model of SLE) were treated with c9,t11-CLA and evaluated for disease progression. Treatment with CLA reduced IL-6 production in cultured mesangial cells, but not in siRNA-treated mesangial cells, supporting a PPAR-γ-mediated mechanism. CLA treatment increased both Transforming Growth Factor (TGF-β) and Interleukin-1 Receptor Antagonist (IL-1RA) mRNA expression independent of PPAR--γ. While CLA treatment reduced nitrite production and iNOS production to some degree, this was an inconsistent finding. Conversely, in the induced anti-GBM mouse model, CLA treatment increased mesangial cell IL-6 mRNA expression, reduced TGF-β expression, and had no effect on IL-1RA. Moreover, NZM2410/J mice that were fed a c9,t11-CLA-supplemented diet had reduced survival times, increased renal inflammation and increased serum IgG2a relative to controls. Taken together, these studies indicate that the in vitro MES13 cell line does not translate to the in vivo mouse model of anti-GBM induced glomerulonephritis. Furthermore, while CLA may have beneficial effects in other mouse models, it worsens disease in NZM2410/J mice. Findings from these models should be interpreted with caution. / Ph. D.

Recent work in humans with protein losing nephropathies has revealed increased urine concentrations of sulfated glycosaminoglycans (GAGs). Differences exist between normal patients, those with glomerulonephritis (GN), and those with amyloidosis thus potentially allowing differentiation without a renal biopsy. Aims of this study were to validate a simple spectrophotometric assay used to measure canine urinary GAGs, establish a normal reference range, and determine optimal storage conditions. Urine GAG concentrations were measured in a limited number of dogs with glomerulonephritis or amyloidosis. Fourteen healthy dogs were placed in metabolic cages and all urine was collected for 24 hours. Serum and urine creatinine concentrations were measured at the beginning and end of the collection period. Urine collected at the beginning of the 24-hr period was centrifuged and the supernatant used to measure a spot GAG concentration and a spot glycosaminoglycan to creatinine ratio (GCR). A well mixed aliquot of the 24-hr sample was centrifuged, the supernatant used to measure the 24-hr total GAG, and stored at 4°C and -20°C for 1, 7, and 30 days. All dogs were used to determine effects of time and temperature (n=14), however, only dogs with an endogenous creatinine clearance > 2 ml/min/kg (n=10) were used to determine normal values. A standard absorption curve using a 1,9-dimethlymethylene blue dye and dilutions of chondroiton-4-sulfate was developed to estimate total GAG concentration. Repeated measures analysis of variance was used to test for effects of storage temperature and time on stability of urinary GAG. A p-value of < 0.05 was considered significant. Relationships between spot urinary GAG concentration, spot urinary GAG to creatinine ratio (GCR) and 24-hr total GAG excretion were estimated using simple linear regression. Single urine samples were collected by cystocentesis from dogs with GN or renal amyloidosis. The diagnosis was confirmed by clinical evaluation or by histologic analysis. Urine protein, creatinine and GAG concentrations were measured. There were no time or temperature effects on urine GAG concentrations for up to 1 day at 4°C and 30 days at -20°C. Mean 24-hr total GAG excretion ± standard deviation was 1.586 ± 0.461 mg/kg of body weight. Mean spot GAG concentration and spot GCR were 5.007 ± 1.588 mg/dl and 0.023 ± 0.01 respectively. Neither spot GAG concentration (R2=0.4216) nor GCR (R2= 0.0839) were adequate predictors of 24-hr total GAG. The GCR's from dogs with renal disease were not different from normal dogs. This study established normal total urinary GAG values in dogs. Contrary to findings in humans, there was no correlation between 24-hr total sulfated GAG and spot GCR in dogs, limiting clinical utility of this test. Further work is needed to determine if either total sulfated GAG or the spot GCR can be used to differentiate causes of protein-losing nephropathies in dogs. / Master of Science

published_or_final_version / abstract / Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Zoology / Doctoral / Doctor of Philosophy

published_or_final_version / Pharmacology / Master / Master of Philosophy

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