La néphropathie à IgA (IgAN), est une maladie glomérulaire chronique primitive et principale cause d'insuffisance rénale dans le monde. Les causes et les facteurs aboutissant aux dépôts des complexes d'IgA1 sont inconnus. La forme soluble du récepteur (CD89s) complexée aux IgA joue un rôle clé dans la pathogenèse de cette maladie. Actuellement, aucun traitement spécifique n'est disponible et les options thérapeutiques sont limitées. La compréhension des mécanismes de la formation de ces complexes permettra d'envisager de nouvelles approches thérapeutiques. Dans cette perspective la première partie de cette thèse, met en évidence l'implication d'une protéine essentielle au développement de la N-IgA, la TG2, dans la régulation du clivage du CD89, et cela par la répression de la sérine phosphatase PP2A et l'activation de la métalloprotéase matricielle MMP-9. Dans les monocytes de patients l'expression diminuée de PP2A est associée à une tendance à l'augmentation de TG2, et inversement corrélée avec l'augmentation des complexes IgA1-CD89s. Afin de cibler ces complexes pathogéniques, un essai préclinique a été réalisé avec une protéase recombinante d'origine bactérienne clivant spécifiquement les IgA1 (IgA1-P). Les résultats ont formellement démontré la spécificité et l'efficacité de la protéase dans la réduction des complexes circulants et des dépôts d'IgA1 dans le modèle humanisé de N-IgA, associée à une diminution des marqueurs de l'inflammation et de l'hématurie. Les résultats ont mis en évidence le rôle de la dérégulation de l'axe TG2-PP2A-MMP-9 dans la formation des complexes IgA1-CD89s lors de la N-IgA, ainsi que l'efficacité de l'IgA1-P à éliminer ces complexes. Ces travaux suggèrent en plus du potentiel thérapeutique promoteur de l'IgA1-P, trois éventuelles cibles thérapeutiques envisageables pour la N-IgA. / IgA nephropathy (IgAN) is a mesangial proliferative primary glomerulonephritis and a major cause of end-stage renal disease. Causes and factors leading to mesangial IgA1 deposition are unknown. The soluble form of the receptor (sCD89) complexed with IgA plays a key role in the pathogenesis of the disease. There is currently no specific treatment available and the therapeutic options are limited. A better comprehension of the mechanisms regulating the formation of IgA1-sCD89 complexes will unveil new strategies for targeted therapies. In this perspective, the first part of this thesis highlights the implication of the transglutaminase 2 (TG2), a protein essential for the development of IgAN, in the regulation of CD89 cleavage, in a mechanism involving the repression of the serine phosphatase PP2A and the activation of the matrix metalloproteinase MMP-9. While a trend towards TG2 increase is observed, PP2A expression is reduced in monocytes obtained from IgAN patients compared to controls, and inversely correlates with the levels of circulating hIgA1-sCD89 complexes. In order to target these pathogenic complexes, a preclinical assay has been performed with a recombinant protease, a bacterial protein that selectively cleaves human IgA1 (IgA1-P). Results formally demonstrate the specificity and the efficacy of the IgA1-P in the reduction of circulating complexes and mesangial IgA1 deposition in a humanized mouse model of IgAN, associated with a reduction in inflammation and hematuria. Concluding, the results presented in this thesis show a role for the TG2-PP2A-MMP-9 axis in the dysregulated formation of IgA1-sCD89 complexes during IgAN development, as well as the effectiveness of IgA1-P in the elimination of these complexes. In addition to the potential therapeutic use of IgA1-P, this work suggests the TG2-PP2A-MMP-9 axis as a new therapeutic candidate for IgAN treatment.

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most used drugs in equine medicine, mainly used to treat inflammation, endotoxemia, pain or fever. NSAIDs inhibit cyclooxygenases which induce to synthesize prostanoids. But NSAIDs have side effects to renal functions too. Objectives: The current study was carried out to investigate the effects of the most common used NSAIDs on urinary parameters in horses. Materials and Methods: Thirty healthy horses were used as a control group and 20 horses with left dorsal displacement, left ventral impaction or lameness of using either flunixin meglumine (FM), metamizole (MZ) or phenylbutazone (PHZ) have been assigned to groups 1, 2 or 3, respectively. Creatinine, urea nitrogen, glucose, protein and electrolytes were measured in serum and urine including GGT using an automatic analyzer. Fractional excretions (FE) of sodium, chloride, potassium, calcium, magnesium and inorganic phosphate, in addition to urinary protein (U-Pro):U-Cr and urinary gamma glutamyl transferase (U-GGT):U-Cr ratios were calculated. Urinary mucus and IgA concentrations were measured and their ratios to the urinary creatinine were calculated. The data were statistically analyzed using Shapiro-Wilks test, descriptive statistics, Kruskal-Wallis one-way analysis of variance and Dunn’s test. Significance was set at P £ 0.05. Results: The FEMg was significantly higher in group 3 (P < 0.033) compared to the control group. The U-GGT:U-Cr ratio was also significantly higher in group 3 (P < 0.001) compared with the control group. The U-Pro:U-Cr ratio was significantly higher in groups 1 and 2 (P < 0.007 and P < 0.001, respectively) than in the control group. PHZ group had a significantly increase in mucus:U-Cr ratio (P < 0.005). Significant increases were observed regarding the IgA:U-Cr ratio in groups 1 (P < 0.007) and 2 (P < 0.014). Conclusions: Long-term use of PHZ has an influence on the renal ascending limb of the loop of Henle, and all these drugs could have effects on the proximal tubules. Phenylbutazone causes an increase in urinary mucus secretion, probably as a protective mechanism against the necrotic effect in renal pelvis of PHZ. Parameters such as U-Pro:U-Cr and U-GGT:U-Cr ratios and FEMg are helpful in detecting these renal abnormalities.