PROJECT SUMMARY Patients with idiopathic uric acid nephrolithiasis (IUAN) exhibit multiple features of the metabolic syndrome and the principal pathogenic abnormality of low urine pH. In previously completed NIH-supported studies, we have identified: 1. Increased net acid load to the kidney and reduced ammoniagenesis by the kidney as the key metabolic defects underlying low UpH in humans with IUAN and in rodent models of UA stone risk. 2. that the peroxisome proliferator-activated receptor (PPAR) agonists thiazolidinediones (TZD) improve many of the systemic and urinary abnormalities in IUAN. Preliminary studies show that modest weight loss (~5%) results in further rise in UpH in TZD-treated IUAN patients, and that an intrarenal adiponectin autocrine/paracrine system may mediate TZD-induced rise in renal ammoniagenesis and urine pH. Based on these findings, we will test three hypotheses with three specific aims. Hypothesis 1: Weight loss + TZD independently and additively result in durable changes in urine chemistry. In Aim 1, we will compare TZD, weight loss or both in combination on urine acid-base parameters relevant to UA stone risk in IUAN patients. Hypothesis 2: While systemic TZD certainly have beneficial effects through multiple mechanisms. There may be direct effects of TZD on the renal tubule to alter urine acid-base parameters and reduces UA stone risk since PPAR is highly expressed in the proximal tubule. In Aim 2, PPAR will be deleted from the renal tubules and the therapeutic effects of TZD will be evaluated. Hypothesis 3: Activation of the recently discovered intrarenal adiponectin system in the renal tubules mediates PPAR activation-induced changes in urinary parameters. In Aim 3, we will test the linear model of PPAR activation → adiponectin activation → increased ammoniagenesis, we will genetically manipulate renal PPAR and adiponectin using knock-out of each to test for necessity, and overexpression of each to test for sufficiency. We will follow with primary cultured renal tubule cells from these animals to further confirm the linear model in vitro. In summary, this proposal combined bench and clinical research to test a new model of how PPAR activation improves urinary UA stone risk via activation of the newly discovered intrarenal adiponectin system, and a novel regimen of TZD and weight loss in treating human IUAN.