Developmental Programming of Kidney Disease by Maternal Diabetes Mellitus---The Role of ADMA

Many chronic diseases such as chronic kidney disease (CKD) and type 2 diabetes might be originated during early life. Evidence from human and animal studies suggests that maternal nutrition can induce developmental programming of adult kidney disease in offspring. It is mainly due to reduced nephron number and glomerular hypertrophy, which are attributed to the imbalance between nitric oxide (NO) and reactive oxygen species (ROS) for nephrogenesis (Bagby SP, 2007). Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, is elevated in CKD and DM. Since NO deficiency is involved in the development of CKD (Baylis C, 2006) and since we found increased ADMA and oxidative stress might cause NO deficiency in CKD (Tain et al, 2007), we hypothesize that maternal diabetes causes the increase of ADMA resulting in reduced nephrons and the development of adult kidney disease in offspring. That hypothesis is based on the following observations. First, ADMA levels are elevated in diabetes and CKD. The increase of ADMA is mainly due to increased PRMT1 (AMDA-synthesizing enzyme) and decreased DDAH (ADMA-degrading enzyme) (Tain et al., 2007). Second, reduced nephron numbers associated with low birth weight could increase risk of CKD (Brenner et al., 1994). Third, PRMT1 is a major enzyme involved in epigenetic modification. However, epigenetic modification induces renal apoptosis and reduces nephron number in the IUGR rat kidney (Pham et al., 2003). Fourth, DDAH activity can be inhibited by oxidative stress and advanced glycation products (AGE), which both are key mechanisms of diabetic complications. Based on these observations, we intend to elucidate whether ADMA is a major target in developmental programming of adult kidney disease in offspring of diabetic mother using a neonatal Streotozotosin (STZ)-induced type 2 diabetes rat model. We also intend to evaluate the effect of PRMT1 on nephrogenesis and AGE/hyperglycemia on DDAH activity using metanephric organ culture and NRK-52E cells in vitro. The vulnerability of kidney disease will be determined by analyzing the association between renal outcome and ADMA pathway at different time points in the development of adult kidney disease. Moreover, manipulation of ADMA by citrulline supplementation and knockdown PRMT1 will be assessed to prevent programmed nephrogenesis and adult kidney disease. The specific aims are designed to provide a comprehensive assessment of ADMA pathway in maternal diabetes-induced disease vulnerability to kidney disease for the offspring: 1) Characterize the role of ADMA, PRMT1, and DDAH in maternal diabetes-induced adult kidney disease. 2) Investigate whether PRMT1 impairs nephrogenesis in maternal diabetes-induced adult kidney disease. 3) Investigate whether hyperglycemia and advanced glycation products (AGE) inhibit DDAH in maternal diabetes-induced adult kidney disease. 4) Manipulate ADMA pathway to prevent maternal diabetes-induced adult kidney disease in offspring. Although advances in the management of diabetic mother have reduced the rate of morbidity and mortality in offspring, less attention has been paid to their long-term sequelae. Accomplishing the specific aims outlined in this proposal will provide the therapeutic approaches to reduce ADMA and reduce the risk of kidney disease in infants of maternal diabetes in later life.

Project ID:PC9808-0757
External Project ID:NSC98-2314-B182-066-MY3