S-16-6: NATRIURETIC PEPTIDES AND HUMORAL FACTORS IN CARDIORENAL SYNDROME AND RESISTANT HYPERTENSION

Abstract

Hypertension is one of the strongest and modifiable risk factors for cardiovascular disease, and a variety of antihypertensive agents and treatment modalities have been developed in these 6 decades. In Japan, however, among the patients with hypertension, ∼75% fail to reach an optimal goal of target blood pressure, and 10–15% of the patients are referred to as resistant hypertension. There are a number of factors for resistant hypertension; especially, the prevalence of resistant hypertension is reported to be 2–3 times higher in patients with chronic kidney disease (CKD) than in the general hypertensive population. CKD has become a major challenge to public health all over the world, and one of the reasons for increased morbidity should be the increasing prevalence of cardiometabolic (or metabolic kidney) disease including diabetic kidney disease. Considering them, novel therapeutic strategies are eagerly being sought. We have studied the roles of vasoactive hormones, such as natriuretic peptides and aldosterone, and local humoral regulators in the pathophysiology of CKD. We have especially focused on metabolic renal disease, including diabetic nephropathy, nephrosclerosis, and renal fibrosis as their common consequence. Using genetically engineered mouse models, we demonstrated the renoprotective role of natriuretic peptides (ANP, BNP) against diabetic nephropathy, immune-mediated renal injury as well as renal fibrosis by subtotal renal ablation. Furthermore, using natriuretic peptide receptor (GC-A)-deficient mice coupled with aldosterone-induced renal injury, we found a renoprotective role of natriuretic peptides on podocytes independent of their antihypertensive action, by inhibiting the local RAS-MAPK-cytokine cascade activation. From recent GWAS analyses, gene polymorphisms related to the natriuretic peptide system are found to be strongly associated with hypertension and cardiovascular disease, suggesting their critical role in cardiovascular homeostasis and blood pressure control. Angiotensin receptor-neprilysin inhibitor (ARNI) is a new class of anti-hypertensive agents characterized by its dual action with renin-angiotensin system blockade and inhibition of natriuretic peptide degradation. In recent clinical trials, ARNI has been shown to have significant cardio-renoprotective effects with a potent antihypertensive property. These findings together could show potential molecular targets, providing a promise for novel therapeutic approaches against CKD with resistant hypertension, metabolic renal disease and related cardiovascular complications.