Therapeutic potential of Zinc-alpha2-Glycoprotein (AZGP1) in chronic kidney and heart disease

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Zinc-alpha2-glycoprotein (AZGP1) is a 41 kDa secreted protein that is expressed in many different tissues. Pleiotropic bioeffects have been described for AZGP1, but the physiological function has not been conclusively clarified. Circulating AZGP1 is eliminated via the kidney so that increased serum AZGP1 serum levels occur in patients with chronic kidney disease. We have observed in siRNA knockdown studies that AZGP1 plays an important role in the regulation of the renal repair response. In the context of acute damage, kockdown of AZGP1 resulted in increased tubular dedifferentiation and increased interstitial fibrosis. These findings indicated a nephroprotective, anti-fibrotic effect of the protein. The analysis of genetically deleted AZGP1-/- mice in different renal damage models confirmed these effects. To elucidate therapeutic perspectives, we have tested the exogenous application of AZGP1 in preliminary studies and found that recombinant AZGP1 protects epithelial integrity and inhibits pro-fibrotic processes. In vitro, AZGP1 antagonized TGF-beta-dependent activation of renal epithelial cells and fibroblasts. We also found a similar mechanism of protection in the heart using the model of aorto-constrictive cardiac hypertrophy (TAC). In the present application we want to verify and expand these findings. For this purpose, we want to test the protective effect of exogenous AZGP1 in various stress models of the kidney (unilateral ureteral obstruction, aristolochic acid nephropathy, ischemia/reperfusion, transgenic TGF-beta over-expression) and the heart (TAC). In parallel, a transgenic strategy for the conditional over-expression of AZGP1 is to be used to test the effects of individual AZGP1 levels and to assess differences in AZGP1 activity depending on the tissue where it is synthesized. Finally, in a first translational step, correlation analyzes are to be carried out to determine the protective significance of AZGP1 in patients with kidney disease. For this purpose, we will perform a prospective cohort study in dialysis patients to evaluate the predictive value of AZGP1 for cardiovascular mortality and morbidity. Furthermore, we will analyze the correlation between serum AZGP1 and transplant outcome in kidney allograft recipients. Overall, we expect that the results of the requested program will not only improve our basic understanding of the role of AZGP1 but will also allow us to make a realistic estimation of the potential of this protein for therapeutic purposes.