This study will identify the role of PACAP (pituitary adenylate cyclase-activating polypeptide) deficiency in patients with nephrotic syndrome. PACAP is a neuropeptide that has a putative role as an inhibitor of megakaryopoiesis and platelet function. Additionally, some studies demonstrate its protective effect on the renal proximal tubule. Patients with nephrotic syndrome show decreased PACAP plasma levels, due to urinary loss. We hypothesize that in severe nephrotic syndrome, plasma deficiency of PACAP enhances megakaryopoiesis and causes blood platelet activation, which contribute to the increased rate of thromboembolic disease in these patients. Next, PACAP deficiency in peritubular capillaries might have a negative effect on proximal tubular function and enhance progression of the interstitial renal damage.
To test our hypothesis, we will address three main key-objectives. First, the role of PACAP deficiency on pro-thrombotic state in patients with nephrotic syndrome will be studied using patient blood and urine samples. Secondly, the influence of PACAP on the kidney in health and in nephrotic syndrome will be examined, using human renal cell lines and human kidney material. Finally, we will study the role of PACAP on pro-thrombotic state and renal disease progression in vivo, using selected animal models of nephrotic syndrome.