The antidiuretic hormone vasopressin (AVP), acting through its type 2 receptor (V ₂ R) in the collecting duct (CD), critically controls urine concentrating capability. Here, we report that site-1 protease–derived (S1P-derived) soluble (pro)renin receptor (sPRR) participates in regulation of fluid homeostasis via targeting V ₂ R. In cultured inner medullary collecting duct (IMCD) cells, AVP-induced V ₂ R expression was blunted by a PRR antagonist, PRO20; a PRR-neutralizing antibody; or a S1P inhibitor, PF-429242. In parallel, sPRR release was increased by AVP and reduced by PF-429242. Administration of histidine-tagged sPRR, sPRR-His, stimulated V ₂ R expression and also reversed the inhibitory effect of PF-429242 on the expression induced by AVP. PF-429242 treatment in C57/BL6 mice impaired urine concentrating capability, which was rescued by sPRR-His. This observation was recapitulated in mice with renal tubule–specific deletion of S1P. During the pharmacological or genetic manipulation of S1P alone or in combination with sPRR-His, the changes in urine concentration were paralleled with renal expression of V ₂ R and aquaporin-2 (AQP2). Together, these results support that S1P-derived sPRR exerts a key role in determining renal V ₂ R expression and, thus, urine concentrating capability.

Although considerable success has been shown for antihypertensive medications, the resistant hypertension and hypertension-related organ damages are still the important clinical issues and pose as high health and economic pressure. Therefore, novel therapeutic techniques and antihypertensive drugs are needed to advance more effective therapy of hypertension and hypertension-related disease to ameliorate mortality and healthcare costs worldwide. In this review, we highlight the latest progress in supporting the therapeutic potential of Elabela (ELA), a recently discovered early endogenous ligand for G-protein-coupled receptor apelin peptide jejunum, apelin receptor. Systemic administration of ELA exerts vasodilatory, antihypertensive, cardioprotective, and renoprotective effects, whereas central application of ELA increases blood pressure and causes cardiovascular remodeling primarily secondary to the hypertension. In addition, ELA drives extravillous trophoblast differentiation and prevents the pathogenesis of preeclampsia (a gestational hypertensive syndrome) by promoting placental angiogenesis. These findings strongly suggest peripheral ELA's therapeutic potential in preventing and treating hypertension and hypertension-related diseases including cardiovascular disease, kidney disease, and preeclampsia. Since therapeutic use of ELA is mainly limited by its short half-life and parenteral administration, it may be a clinical application candidate for the therapy of hypertension and its complications when fused with a large inert chemicals (e.g. polyethylene glycol, termed polyethylene glycol-ELA-21) or other proteins (e.g. the Fc fragment of IgG and albumin, termed Fc-ELA-21 or albumin-ELA-21), and new delivery methods are encouraged to develop to improve the efficacy of ELA fragments on apelin peptide jejunum or alternative unknown receptors.

The therapies available for management of obesity and associated conditions are limited, because they are often directed toward an individual component of metabolic syndrome and are associated with adverse effects. Here, we report the multifaceted therapeutic potential of histidine-tagged recombinant soluble (pro)renin receptor (sPRR), termed sPRR-His, in a mouse model of diet-induced obesity (DIO). In the DIO model, 2-week administration of sPRR-His lowered body weight and remarkably improved multiple metabolic parameters in the absence of fluid retention. Conversely, inhibition of endogenous sPRR production by PF429242 induced diabetes and insulin resistance, both of which were reversed by the sPRR-His supplement. At the cellular level, sPRR-His enhanced insulin-induced increases in glucose uptake via upregulation of phosphorylated AKT and protein abundance of glucose transporter 4. Promoter and gene expression analysis revealed PRR as a direct target gene of PPAR γ . Adipocyte-specific PPAR γ deletion induced severe diabetes and insulin resistance associated with reduced adipose PRR expression and circulating sPRR. The sPRR-His supplement in the null mice nearly normalized blood glucose and insulin levels. Additionally, sPRR-His treatment suppressed DIO-induced renal sodium-glucose cotransporter-2 (SGLT2) expression. Overall, sPRR-His exhibits a therapeutic potential in management of metabolic syndrome via interaction with PPARγ.

Endothelial inflammation is a multifaceted physiological process that plays a pivotal role in the pathogenesis and progression of diverse diseases, encompassing but not limited to acute lung infections like COVID-19, coronary artery disease, stroke, sepsis, metabolic syndrome, certain malignancies, and even psychiatric disorders such as depression. This inflammatory response is characterized by augmented expression of adhesion molecules and secretion of pro-inflammatory cytokines. In this study, we discovered that saponins from Allium macrostemon bulbs (SAMB) effectively inhibited inflammation in human umbilical vein endothelial cells induced by the exogenous inflammatory mediator lipopolysaccharide or the endogenous inflammatory mediator tumor necrosis factor-α, as evidenced by a significant reduction in the expression of pro-inflammatory factors and vascular cell adhesion molecule-1 (VCAM-1) with decreased monocyte adhesion. By employing the NF-κB inhibitor BAY-117082, we demonstrated that the inhibitory effect of SAMB on VCAM-1 expression may be attributed to the NF-κB pathway’s inactivation, as characterized by the suppressed IκBα degradation and NF-κB p65 phosphorylation. Subsequently, we employed a murine model of lipopolysaccharide-induced septic acute lung injury to substantiate the potential of SAMB in ameliorating endothelial inflammation and acute lung injury in vivo. These findings provide novel insight into potential preventive and therapeutic strategies for the clinical management of diseases associated with endothelial inflammation.

(Pro)renin receptor (PRR) is highly expressed in the distal nephron, but it has an unclear functional implication. The present study was conducted to explore a potential role of renal PRR during high K⁺ (HK) loading. In normal Sprague-Dawley rats, a 1-wk HK intake increased renal expression of full-length PRR and urinary excretion of soluble PRR (sPRR). Administration of PRO20, a decoy peptide antagonist of PRR, in K⁺-loaded animals elevated plasma K⁺ level and decreased urinary K⁺ excretion, accompanied with suppressed urinary aldosterone excretion and intrarenal aldosterone levels. HK downregulated Na⁺-Cl⁻ cotransporter (NCC) expression but upregulated CYP11B2 (cytochrome P-450, family 11, subfamily B, polypeptide 2), renal outer medullary K⁺ channel (ROMK), calcium-activated potassium channel subunit α₁ (α-BK), α-Na⁺-K⁺-ATPase (α-NKA), and epithelial Na⁺ channel subunit β (β-ENaC), all of which were blunted by PRO20. After HK loading was completed, urinary, but not plasma renin, was upregulated, which was blunted by PRO20. The same experiments that were performed using adrenalectomized (ADX) rats yielded similar results. Interestingly, spironolactone treatment in HK-loaded ADX rats attenuated kaliuresis but promoted natriuresis, which was associated with the suppressed responses of β-ENaC, α-NKA, ROMK, and α-BK protein expression. Taken together, we discovered a novel role of renal PRR in regulation of K⁺ homeostasis through a local mechanism involving intrarenal renin-angiotensin-aldosterone system and coordinated regulation of membrane Na⁺- and K⁺-transporting proteins.

Background: The collecting duct (CD) is a major site of both biosynthesis and action of prostaglandin E ₂ as highlighted by the predominant expression of COX-2 (cyclooxygenase-2) and some E-prostanoid (EP) subtypes at this nephron site. The purpose of this study was to determine the relevance and mechanism of CD COX-2/prostaglandin E ₂ /EP ₁ signaling for the regulation of Na ⁺ hemostasis during Na ⁺ depletion. Methods: Mice with Aqp2Cre-driven deletion of COX-2 (COX-2 ^fl/fl Aqp2Cre ⁺ ) or the EP ₁ subtype (EP ₁ ^fl/fl Aqp2Cre ⁺ ) were generated and the Na ⁺ -wasting phenotype of these mice during low-salt (LS) intake was examined. EP subtypes responsible for prostaglandin E ₂ -induced local renin response were analyzed in primary cultured mouse inner medullary CD cells. Results: Following 28-day LS intake, COX-2 ^fl/fl Aqp2Cre ⁺ mice exhibited a higher urinary Na ⁺ excretion and lower cumulative Na ⁺ balance, accompanied with suppressed intrarenal renin, AngII (angiotensin II), and aldosterone, expression of CYP11B2 (cytochrome P450 family 11 subfamily B member 2), and blunted expression of epithelial sodium channel subunits compared to floxed controls (COX-2 ^fl/fl Aqp2Cre ⁻ ), whereas no differences were observed for indices of systemic renin-angiotensin-aldosterone system. In cultured CD cells, exposure to prostaglandin E ₂ stimulated release of soluble (pro)renin receptor, prorenin/renin and aldosterone and the stimulation was more sensitive to antagonism of EP ₁ as compared other EP subtypes. Subsequently, EP ₁ ^fl/fl Aqp2Cre ⁺ mice largely recapitulated Na ⁺ -wasting phenotype seen in COX-2 ^fl/fl Aqp2Cre ⁺ mice. Conclusions: The study for the first time reports that CD COX-2/EP ₁ pathway might play a key role in maintenance of Na ⁺ homeostasis in the face of Na ⁺ depletion, at least in part, through activation of intrarenal renin-angiotensin-aldosterone-system and epithelial sodium channel.