ADMA/NO pathway in the developmental programming of kidney disease and hypertension

Both chronic kidney disease (CKD) and hypertension are highly prevalent diseases globally. These chronic diseases might originate during early life. Pre-, peri-, or post-natal insults can elicit epigenetic alterations in gene for organogenesis, morphological changes, and adaptive physiological responses, leading to chronic disease in later life. The kidney was identified as a key player in the developmentally programmed hypertension, mainly by reduced nephron endowment and impaired sodium excretion. Oxidative stress, mainly caused by the imbalanced ˙NO/˙O2 - system, has been proposed to contribute to the development of kidney disease and hypertension. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, level is elevated in patients with CKD and hypertension. Superoxide can induce ADMA production, whereas ADMA can uncouple NOS leading to oxidative stress burden. Thereby, ADMA might be as a major player involved in NO/O2 - imbalance, resulting in developmental programming. We recently found that maternal caloric restriction (CR) causes ADMA increases resulting in kidney disease and hypertension in the offspring, which can be prevented by L-citrulline (the precursor of L-arginine) supplementation. In addition to CR model, pre-eclampsia is a commonly used model to study developmental programming. Pre-eclampsia is still a major cause of maternal mortality and intrauterine growth retardation. Thereby, we intend to use 3 different animal models, including maternal CR model, ADMA-treated pregnant rat model, and suramin-induced preeclampsia model, to elucidate whether ADMA is a common pathway in developmental programming of kidney disease and hypertension. The major research goal of this study is to target on ADMA to prevent developmental programming of kidney disease and hypertension. Four different but concurrently run sets of experiments aim to advance our understanding of ADMA/NO pathway on developmental programming. The four approaches are: 1) The use of 3 different animal models to elucidate whether ADMA is a common pathway in developmental programming; 2) The discovery of genes related to nephrogenesis (e.g., BMP4), apoptosis (e.g., p53), and natriuresis (e.g., NKCC2) which are epigenetic modifications by ADMA and PRMT-1 (ADMA-synthesizing enzyme); 3) The identification of epigenetic biomarkers in the kidney, placenta, and blood for early diagnosis of individuals with higher risks for kidney disease and hypertension; and 4) The development of novel therapeutic approaches targeting on ADMA/NO pathway (e.g., citrulline supplementation) to prevent kidney disease and hypertension in the offspring. The specific aims are designed to provide a comprehensive assessment of ADMA/NO pathway at an organ specific level in three different models: 1) To characterize the role of ADMA in maternal caloric restriction-induced adult kidney disease and hypertension. 2) To investigate whether ADMA impairs nephrogenesis in the offspring of ADMA-treated pregnant rat. 3) To investigate whether increased oxidative stress inhibit DDAH to increased ADMA in suramin-induced pre-eclampsia model. 4) To reduce ADMA and restore NO/ROS imbalance to prevent developmental programming of kidney disease and hypertension. Toward a better understanding of developmental programming will enable ideal care to reduce the future economic burden of CKD and hypertension in Taiwan.

Project ID:PC10202-0846
External Project ID:NSC101-2314-B182-085-MY3