Renal acid ceramidase-S1P pathway in salt-sensitive hypertension

Sphingolipid metabolites are recently emerging as important lipid signaling molecules. Among them, sphingosine-1-phosphate (S1P) is known to play critical roles in cellular processes in various organ systems including kidneys. S1P receptor (S1PR)1, S1PR2 and S1PR3 as well as S1P-producing enzymes are detected

in the kidneys. S1P system plays important roles in the pathogenesis of many kidney diseases. However, little is known about the role of the S1P system in renal Na+ excretion. We have recently shown that S1P receptors are prominently expressed in the renal medulla; S1P is a novel diuretic factor in the renal medulla and regulates

Na+ excretion via the activation of S1PR1 receptor; S1PR1 in collecting duct is an important antihypertensive pathway by promoting sodium excretion and that impairment of renal medullary S1PR1 contributes to salt- sensitive hypertension. These studies suggest important roles of renal S1P system in salt-sensitive hypertension.

Our previous studies focused on S1PR1 receptor. Apparently, levels of S1P production would play critical roles in the function of S1P system. However, whether enzymes that produce S1P participate in the control of Na+ excretion and blood pressure has not been investigated. Our preliminary studies demonstrated that among the

enzymes that are responsible for the S1P production, acid ceramidase (AC) as the rate-limit enzyme was significantly increased after high salt intake and inhibited in DOCA-salt hypertension. Moreover, infusion of AC inhibitor into renal medulla and knockout of AC in collecting ducts inhibited sodium excretion and increased salt

sensitivity of blood pressure. Based on the above information, the central hypothesis is that high salt-induced AC-S1P pathway in the renal medulla is a novel mechanism to promote the excretion of extra Na+ load and that suppression of renal medullary AC-S1P pathway contributes to the development of salt-sensitive hypertension.

Mechanistically, we characterized the expressions of candidate transcription factors and found that Activating Protein 2α (AP2A) was increased after high salt intake and present in the collecting ducts. It is therefore proposed that AP2A is the upstream signal to activate the expression of AC. Indeed, our preliminary data showed that

transfection of AP2A shRNA into the renal medulla blocked the high salt-induced AC expression and that the high salt-induced AP2A was suppressed in DOCA-salt mice. Three specific aims are proposed. Aim 1: To test the hypothesis that activation of AC-S1P pathway mediates the excretion of extra sodium load and that inhibition

of AC-S1P pathway in the renal medulla impairs renal Na+ handling, thereby enhancing salt sensitivity of blood pressure. Aim 2: To test the hypothesis that the deficiency of AC-S1P pathway contributes to the pathogenesis of salt-sensitive hypertension in DOCA-salt model. Aim 3: To determine the mechanisms causing the deficiency

of AC pathway: test the hypothesis that impairment of transcription factor AP2A leads to the suppression of AC levels in the renal medulla in DOCA-salt hypertension. The proposed studies will reveal a novel molecular mechanism in renal Na+ handling and provide new insights into the pathogenesis of salt-sensitive hypertension.