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BACKGROUND: Despite the known negative consequences of exercise addiction and preliminary evidence suggesting that it may co-occur with other health risk behaviors, no studies to date have examined exercise addiction among college students in conjunction with disordered eating behaviors and alcohol use. The aim of this study was to describe which college students are most at-risk for co-occurring health risk behaviors to enhance the efficiency of health risk prevention efforts. METHOD: Guided by multidimensional theories of impulsivity and substance use models of comorbidity, this study used latent profile analysis to examine whether separate, conceptually meaningful profiles of risk for exercise addiction, disordered eating behaviors, and alcohol use would emerge among 503 college students from a large public university RESULTS: The best-fitting model supported three profiles. MANOVA results revealed significant profile differences based on exercise addiction, binge eating, purging, laxative/pill/diuretic use, exercising longer than 60 minutes, negative urgency, and problematic alcohol use. Profile 3 students (n = 29), labeled the Affect Driven Health Risk-Takers, demonstrated the highest levels of impulsivity (i.e., negative urgency, lack of premeditation, lack of perseverance, and sensation seeking) and the most risk behaviors compared to the other two profiles. Profile membership was associated with distinct levels of negative urgency, exercise addiction, disordered eating behaviors, and problematic alcohol use. A small proportion of undergraduates demonstrated co-occurring exercise addiction, disordered eating behaviors, and problematic alcohol use. Profile membership also predicted the health outcomes of clinically significant exercise addiction and hazardous alcohol use. CONCLUSIONS: Findings illuminated how patterns of risk behavior engagement were associated with clinically significant exercise addiction and hazardous alcohol use and will inform prevention efforts and clinical interventions with at-risk college students.

Kidneys continuously filter an enormous amount of sodium and adapt kidney Na+ reabsorption to match Na+ intake to maintain circulatory volume and electrolyte homeostasis. Males (M) respond to high-salt (HS) diet by translocating proximal tubule Na+/H+ exchanger isoform 3 (NHE3) to the base of the microvilli, reducing activated forms of the distal NaCl cotransporter (NCC) and epithelial Na+ channel (ENaC). Males (M) and females (F) on normal-salt (NS) diet present sex-specific profiles of “transporters” (cotransporters, channels, pumps, and claudins) along the nephron, e.g., F exhibit 40% lower NHE3 and 200% higher NCC abundance than M. We tested the hypothesis that adaptations to HS diet along the nephron will, likewise, exhibit sexual dimorphisms. C57BL/6J mice were fed for 15 days with 4% NaCl diet (HS) versus 0.26% NaCl diet (NS). On HS, M and F exhibited normal plasma [Na+] and [K+], similar urine volume, Na+, K+, and osmolal excretion rates normalized to body weight. In F, like M, HS lowered abundance of distal NCC, phosphorylated NCC, and cleaved (activated) forms of ENaC. The adaptations associated with achieving electrolyte homeostasis exhibit sex-dependent and independent mechanisms. Sex differences in baseline “transporters” abundance persist during HS diet, yet the fold changes during HS diet (normalized to NS) are similar along the distal nephron and collecting duct. Sex-dependent differences observed along the proximal tubule during HS show that female kidneys adapt differently from patterns reported in males, yet achieve and maintain fluid and electrolyte homeostasis.

The renal nephron consists of a series of distinct cell types that function in concert to maintain fluid and electrolyte balance and blood pressure. The renin-angiotensin system (RAS) is central to Na(+) and volume balance. We aimed to determine how loss of angiotensin II signaling in the proximal tubule (PT), which reabsorbs the bulk of filtered Na(+) and volume, impacts solute transport throughout the nephron. We hypothesized that PT renin-angiotensin system disruption would not only depress PT Na(+) transporters but also impact downstream Na(+) transporters. Using a mouse model in which the angiotensin type 1a receptor (AT(1a)R) is deleted specifically within the PT (AT(1a)R PTKO), we profiled the abundance of Na(+) transporters, channels, and claudins along the nephron. Absence of PT AT(1a)R signaling was associated with lower abundance of PT transporters (Na(+)/H(+) exchanger isoform 3, electrogenic Na(+)-bicarbonate cotransporter 1, and claudin 2) as well as lower abundance of downstream transporters (total and phosphorylated Na(+)-K(+)-2Cl(−) cotransporter, medullary Na(+)-K(+)-ATPase, phosphorylated NaCl cotransporter, and claudin 7) versus controls. However, transport activities of Na(+)-K(+)-2Cl(−) cotransporter and NaCl cotransporter (assessed with diuretics) were similar between groups in order to maintain electrolyte balance. Together, these results demonstrate the primary impact of angiotensin II regulation on Na(+) reabsorption in the PT at baseline and the associated influence on downstream Na(+) transporters, highlighting the ability of the nephron to integrate Na(+) transport along the nephron to maintain homeostasis. NEW & NOTEWORTHY Our study defines a novel role for proximal tubule angiotensin receptors in regulating the abundance of Na(+) transporters throughout the nephron, thereby contributing to the integrated control of fluid balance in vivo.

As the most abundant cation in archaeal, bacterial, and eukaryotic cells, potassium (K

Contains fulltext : 238842.pdf (Publisher’s version ) (Closed access) A major pathway in hypertension pathogenesis involves direct activation of ANG II type 1 (AT(1)) receptors in the kidney, stimulating Na(+) reabsorption. AT(1) receptors in tubular epithelia control expression and stimulation of Na(+) transporters and channels. Recently, we found reduced blood pressure and enhanced natriuresis in mice with cell-specific deletion of AT(1) receptors in smooth muscle (SMKO mice). Although impaired vasoconstriction and preserved renal blood flow might contribute to exaggerated urinary Na(+) excretion in SMKO mice, we considered whether alterations in Na(+) transporter expression might also play a role; therefore, we carried out proteomic analysis of key Na(+) transporters and associated proteins. Here, we show that levels of Na(+)-K(+)-2Cl(-) cotransporter isoform 2 (NKCC2) and Na(+)/H(+) exchanger isoform 3 (NHE3) are reduced at baseline in SMKO mice, accompanied by attenuated natriuretic and diuretic responses to furosemide. During ANG II hypertension, we found widespread remodeling of transporter expression in wild-type mice with significant increases in the levels of total NaCl cotransporter, phosphorylated NaCl cotransporter (Ser(71)), and phosphorylated NKCC2, along with the cleaved, activated forms of the α- and γ-epithelial Na(+) channel. However, the increases in α- and γ-epithelial Na(+) channel with ANG II were substantially attenuated in SMKO mice. This was accompanied by a reduced natriuretic response to amiloride. Thus, enhanced urinary Na(+) excretion observed after cell-specific deletion of AT(1) receptors from smooth muscle cells is associated with altered Na(+) transporter abundance across epithelia in multiple nephron segments. These findings suggest a system of vascular-epithelial in the kidney, modulating the expression of Na(+) transporters and contributing to the regulation of pressure natriuresis.NEW & NOTEWORTHY The use of drugs to block the renin-angiotensin system to reduce blood pressure is common. However, the precise mechanism for how these medications control blood pressure is incompletely understood. Here, we show that mice lacking angiotensin receptors specifically in smooth muscle cells lead to alternation in tubular transporter amount and function. Thus, demonstrating the importance of vascular-tubular cross talk in the control of blood pressure.

Extracellular fluid (ECF) potassium concentration ([K+]) is maintained by adaptations of kidney and skeletal muscle, responses heretofore studied separately. We aimed to determine how these organ systems work in concert to preserve ECF [K+] in male C57BL/6J mice fed a K+-deficient diet (0K) versus 1% K+ diet (1K) for 10 days ( n = 5–6/group). During 0K feeding, plasma [K+] fell from 4.5 to 2 mM; hindlimb muscle (gastrocnemius and soleus) lost 28 mM K+ (from 115 ± 2 to 87 ± 2 mM) and gained 27 mM Na+ (from 27 ± 0.4 to 54 ± 2 mM). Doubling of muscle tissue [Na+] was not associated with inflammation, cytokine production or hypertension as reported by others. Muscle transporter adaptations in 0K- versus 1K-fed mice, assessed by immunoblot, included decreased sodium pump α2-β2 subunits, decreased K+-Cl− cotransporter isoform 3, and increased phosphorylated (p) Na+,K+,2Cl− cotransporter isoform 1 (NKCC1p), Ste20/SPS-1-related proline-alanine rich kinase (SPAKp), and oxidative stress-responsive kinase 1 (OSR1p) consistent with intracellular fluid (ICF) K+ loss and Na+ gain. Renal transporters’ adaptations, effecting a 98% reduction in K+ excretion, included two- to threefold increased phosphorylated Na+-Cl− cotransporter (NCCp), SPAKp, and OSR1p abundance, limiting Na+ delivery to epithelial Na+ channels where Na+ reabsorption drives K+ secretion; and renal K sensor Kir 4.1 abundance fell 25%. Mass balance estimations indicate that over 10 days of 0K feeding, mice lose ~48 μmol K+ into the urine and muscle shifts ~47 μmol K+ from ICF to ECF, illustrating the importance of the concerted responses during K+ deficiency.

Each day, ~1.7 kg of NaCl and 180 liters of water are reabsorbed by nephron segments in humans, with urinary excretion fine tuned to meet homeostatic requirements. These tasks are coordinated by a spectrum of renal Na+transporters and channels. The goal of the present study was to investigate the extent to which inhibitors of transepithelial Na+transport (TNa) along the nephron alter urinary solute excretion and how those effects may vary between male and female subjects. To accomplish that goal, we developed sex-specific multinephron models that represent detailed transcellular and paracellular transport processes along the nephrons of male and female rat kidneys. We simulated inhibition of Na+/H+exchanger 3 (NHE3), bumetanide-sensitive Na+-K+-2Cl−cotransporter (NKCC2), Na+-Cl−cotransporter (NCC), and amiloride-sensitive epithelial Na+channel (ENaC). NHE3 inhibition simulations predicted a substantially reduced proximal tubule TNa, and NKCC2 inhibition substantially reduced thick ascending limb TNa. Both gave rise to diuresis, natriuresis, and kaliuresis, with those effects stronger in female rats. While NCC inhibition was predicted to have only minor impact on renal TNa, it nonetheless had a notable effect of enhancing excretion of Na+, K+, and Cl−, particularly in female rats. Inhibition of ENaC was predicted to have opposite effects on the excretion of Na+(increased) and K+(decreased) and to have only a minor impact on whole kidney TNa. Unlike inhibition of other transporters, ENaC inhibition induced stronger natriuresis and diuresis in male rats than female rats. Overall, model predictions agreed well with measured changes in Na+and K+excretion in response to diuretics and Na+transporter mutations.

The National Heart, Lung, and Blood Institute convened a multidisciplinary working group of hypertension researchers on December 6 to 7, 2018, in Bethesda, MD, to share current scientific knowledge in hypertension and to identify barriers to translation of basic into clinical science/trials and implementation of clinical science into clinical care of patients with hypertension. The goals of the working group were (1) to provide an overview of recent discoveries that may be ready for testing in preclinical and clinical studies; (2) to identify gaps in knowledge that impede translation; (3) to highlight the most promising scientific areas in which to pursue translation; (4) to identify key challenges and barriers for moving basic science discoveries into translation, clinical studies, and trials; and (5) to identify roadblocks for effective dissemination and implementation of basic and clinical science in real-world settings. The working group addressed issues that were responsive to many of the objectives of the National Heart, Lung, and Blood Institute Strategic Vision. The working group identified major barriers and opportunities for translating research to improved control of hypertension. This review summarizes the discussion and recommendations of the working group.

Potassium disorders are common in patients with kidney disease, particularly in patients with tubular disorders and low glomerular filtration rate. A multidisciplinary group of researchers and clinicians met in October 2018 to identify evidence and address controversies in potassium management. The issues discussed encompassed our latest understanding of the regulation of tubular potassium excretion in health and disease; the relationship of potassium intake to cardiovascular and kidney outcomes, with increasing evidence showing beneficial associations with plant-based diet and data to suggest a paradigm shift from the idea of dietary restriction toward fostering patterns of eating that are associated with better outcomes; the paucity of data on the effect of dietary modification in restoring abnormal serum potassium to the normal range; a novel diagnostic algorithm for hypokalemia that takes into account the ascendency of the clinical context in determining cause, aligning the educational strategy with a practical approach to diagnosis; and therapeutic approaches in managing hyperkalemia when chronic and in the emergency or hospital ward. In sum, we provide here our conference deliberations on potassium homeostasis in health and disease, guidance for evaluation and management of dyskalemias in the context of kidney diseases, and research priorities in each of the above areas.

Transmembrane potassium (K) gradients are key determinants of membrane potential that can modulate action potentials, control muscle contractility, and influence ion channel and transporter activity. Daily K intake is normally equal to the amount of K in the entire extracellular fluid (ECF) creating a critical challenge - how to maintain ECF [K] and membrane potential in a narrow range during feast and famine. Adaptations to maintain ECF [K] include sensing the K intake, sensing ECF [K] vs. desired set-point and activating mediators that regulate K distribution between ECF and ICF, and regulate renal K excretion. In this focused review, we discuss the basis of these adaptions, including (1) potential mechanisms for rapid feedforward signaling to kidney and muscle after a meal (before a rise in ECF [K]), (2) how skeletal muscles sense and respond to changes in ECF [K], (3) effects of K on aldosterone biosynthesis, and (4) how the kidney responds to changes in ECF [K] to modify K excretion. The concepts of sexual dimorphisms in renal K handling adaptation are introduced, and the molecular mechanisms that can account for the benefits of a K-rich diet to maintain cardiovascular health are discussed. Although the big picture of K homeostasis is becoming more clear, we also highlight significant pieces of the puzzle that remain to be solved, including knowledge gaps in our understanding of initiating signals, sensors and their connection to homeostatic adjustments of ECF [K].

Extracellular potassium (K+) homeostasis is achieved by a concerted effort of multiple organs and tissues. A limitation in studies of K+ homeostasis is inadequate techniques to quantify K+ fluxes into and out of organs and tissues in vivo. The goal of the present study was to test the feasibility of a novel approach to estimate K+ distribution and fluxes in vivo using stable K+ isotopes. 41K was infused as KCl into rats consuming control or K+-deficient chow ( n = 4 each), 41K-to-39K ratios in plasma and red blood cells (RBCs) were measured by inductively coupled plasma mass spectrometry, and results were subjected to compartmental modeling. The plasma 41K/39K increased during 41K infusion and decreased upon infusion cessation, without altering plasma total K+ concentration ([K+], i.e., 41K + 39K). The time course of changes was analyzed with a two-compartmental model of K+ distribution and elimination. Model parameters, representing transport into and out of the intracellular pool and renal excretion, were identified in each rat, accurately predicting decreased renal K+ excretion in rats fed K+-deficient vs. control diet ( P < 0.05). To estimate rate constants of K+ transport into and out of RBCs, 41K/39K were subjected to a simple model, indicating no effects of the K+-deficient diet. The findings support the feasibility of the novel stable isotope approach to quantify K+ fluxes in vivo and sets a foundation for experimental protocols using more complex models to identify heterogeneous intracellular K+ pools and to answer questions pertaining to K+ homeostatic mechanisms in vivo.

Angiotensin II (ANG II) raises blood pressure partly by stimulating tubular Na+ reabsorption. The effects of ANG II on tubular Na+ transporters (i.e., channels, pumps, cotransporters, and exchangers) vary between short-term and long-term exposure. To better understand the physiological impact, we used a computational model of transport along the rat nephron to predict the effects of short- and long-term ANG II-induced transporter activation on Na+ and K+ reabsorption/secretion, and to compare measured and calculated excretion rates. Three days of ANG II infusion at 200 ng·kg−1·min−1 is nonpressor, yet stimulates transporter accumulation. The increase in abundance of Na+/H+ exchanger 3 (NHE3) or activated Na+-K+-2Cl− cotransporter-2 (NKCC2-P) predicted significant reductions in urinary Na+ excretion, yet there was no observed change in urine Na+. The lack of antinatriuresis, despite Na+ transporter accumulation, was supported by Li+ and creatinine clearance measurements, leading to the conclusion that 3-day nonpressor ANG II increases transporter abundance without proportional activation. Fourteen days of ANG II infusion at 400 ng·kg−1·min−1 raises blood pressure and increases Na+ transporter abundance along the distal nephron; proximal tubule and medullary loop transporters are decreased and urine Na+ and volume output are increased, evidence for pressure natriuresis. Simulations indicate that decreases in NHE3 and NKCC2-P contribute significantly to reducing Na+ reabsorption along the nephron and to pressure natriuresis. Our results also suggest that differential regulation of medullary (decrease) and cortical (increase) NKCC2-P is important to preserve K+ while minimizing Na+ retention during ANG II infusion. Lastly, our model indicates that accumulation of active Na+-Cl− cotransporter counteracts epithelial Na+ channel-induced urinary K+ loss.

This review highlights the gaps in knowledge and methodological challenges discussed during the Experimental Biology 2019 expert panel session titled "Moving the Needle on Hypertension: What Knowledge Is Needed?" Hypertension is a critical public health burden. Despite a demonstrated benefit of blood pressure reduction on measures of hypertension-related morbidity and mortality, rates for successful blood pressure control remain low. Dietary sodium reduction has been shown to reduce both systolic blood pressure by approximately 3.2 mm Hg and diastolic blood pressure by 2.3 mm Hg, depending on baseline blood pressure and degree of sodium reduction. The updated Dietary Reference Intakes for adults released by the National Academies of Sciences, Engineering, and Medicine include a Chronic Disease Risk Reduction sodium intake level of 2300 mg/d, highlighting the importance of dietary sodium intake in reducing elevated blood pressure and indicating that reducing intakes to this level is expected to reduce blood pressure and risk of cardiovascular disease. The average US daily sodium intake of 3400 mg/d is well above the Chronic Disease Risk Reduction of 2300 mg/d, suggesting that dietary sodium reduction has the potential to significantly improve public health. Although the National Academies of Sciences, Engineering, and Medicine report presents intake recommendations based on a systematic, comprehensive, and thorough evaluation of the evidence, several challenges to moving the needle on hypertension remain. Success will require a more advanced understanding of sodium and potassium physiology, as well as development of the tools needed to effectively address existing research gaps and reduce barriers to sodium intake reduction.

Raising blood pressure stimulates pressure natriuresis (P-Nat). In males (M) Sprague Dawley rats (SDR), Na + reabsorption (T Na ) is acutely reduced by retraction of proximal tubule (PT) NHE3 to microvillar base and NaPi2 internalization. In females (F), at baseline PT NHE3 is already at microvillar base and NaPi2 is less abundant than in M. We AIM to determine characteristics and mechanisms of P-Nat in F (vs M) rats. Methods: Inactin anesthetized F and M SDR (n=5/group) were provoked by vasoconstriction (or sham). Mean arterial pressure (MAP) was recorded via carotid artery, urine collected via bladder, Na + transporters’ abundance assessed via immunoblot and localization by immunohistochemistry. Results (Fig 1A): Baseline MAP (mmHg) was lower in F vs. M (91 ± 5 vs.105 ± 3, P =0.04) while urine volume (UV) and electrolyte excretion (UNaV, UKV) were similar. After celiac and mesenteric bed constriction, MAP rose to 128 ± 3 mmHg in both sexes; UNaV, UV and C Na increased 12 to 15-fold in F (all P P >0.08). Constriction of abdominal aorta further raised UNaV in F with less impact in M. Na + transporters . In F, NHE3 remained at PT microvillar base and NaPi2 was internalized with vasoconstriction. NHE3P (indicating inactivation) abundance increased 29% in F, P =0.058. Lithium clearance, measure of volume flow leaving early nephron, increased 9-fold in F ( P =0.02) vs. 5-fold in M ( P =0.07). F mTAL NHE3, NKCC2p, and SPAKp (co-transporter kinase) abundances were 22, 24, and 43% lower vs shams ( ANOVA P Summary: F vs M SDR exhibit more robust P-Nat associated with less T Na in early nephron and reductions in PT-mTAL Na + transporters, consistent with higher UNaV at any given BP (Fig 1B).

Extracellular fluid (ECF) potassium concentration ([K(+)]) is maintained by adaptations of kidney and skeletal muscle, responses heretofore studied separately. We aimed to determine how these organ systems work in concert to preserve ECF [K(+)] in male C57BL/6J mice fed a K(+)-deficient diet (0K) versus 1% K(+) diet (1K) for 10 days (n = 5–6/group). During 0K feeding, plasma [K(+)] fell from 4.5 to 2 mM; hindlimb muscle (gastrocnemius and soleus) lost 28 mM K(+) (from 115 ± 2 to 87 ± 2 mM) and gained 27 mM Na(+) (from 27 ± 0.4 to 54 ± 2 mM). Doubling of muscle tissue [Na(+)] was not associated with inflammation, cytokine production or hypertension as reported by others. Muscle transporter adaptations in 0K- versus 1K-fed mice, assessed by immunoblot, included decreased sodium pump α2-β2 subunits, decreased K(+)-Cl(−) cotransporter isoform 3, and increased phosphorylated (p) Na(+),K(+),2Cl(−) cotransporter isoform 1 (NKCC1p), Ste20/SPS-1-related proline-alanine rich kinase (SPAKp), and oxidative stress-responsive kinase 1 (OSR1p) consistent with intracellular fluid (ICF) K(+) loss and Na(+) gain. Renal transporters’ adaptations, effecting a 98% reduction in K(+) excretion, included two- to threefold increased phosphorylated Na(+)-Cl(−) cotransporter (NCCp), SPAKp, and OSR1p abundance, limiting Na(+) delivery to epithelial Na(+) channels where Na(+) reabsorption drives K(+) secretion; and renal K sensor Kir 4.1 abundance fell 25%. Mass balance estimations indicate that over 10 days of 0K feeding, mice lose ~48 μmol K(+) into the urine and muscle shifts ~47 μmol K(+) from ICF to ECF, illustrating the importance of the concerted responses during K(+) deficiency.

Each day, ~1.7 kg of NaCl and 180 liters of water are reabsorbed by nephron segments in humans, with urinary excretion fine tuned to meet homeostatic requirements. These tasks are coordinated by a spectrum of renal Na(+) transporters and channels. The goal of the present study was to investigate the extent to which inhibitors of transepithelial Na(+) transport (T(Na)) along the nephron alter urinary solute excretion and how those effects may vary between male and female subjects. To accomplish that goal, we developed sex-specific multinephron models that represent detailed transcellular and paracellular transport processes along the nephrons of male and female rat kidneys. We simulated inhibition of Na(+)/H(+) exchanger 3 (NHE3), bumetanide-sensitive Na(+)-K(+)-2Cl(−) cotransporter (NKCC2), Na(+)-Cl(−) cotransporter (NCC), and amiloride-sensitive epithelial Na(+) channel (ENaC). NHE3 inhibition simulations predicted a substantially reduced proximal tubule T(Na), and NKCC2 inhibition substantially reduced thick ascending limb T(Na). Both gave rise to diuresis, natriuresis, and kaliuresis, with those effects stronger in female rats. While NCC inhibition was predicted to have only minor impact on renal T(Na), it nonetheless had a notable effect of enhancing excretion of Na(+), K(+), and Cl(−), particularly in female rats. Inhibition of ENaC was predicted to have opposite effects on the excretion of Na(+) (increased) and K(+) (decreased) and to have only a minor impact on whole kidney T(Na). Unlike inhibition of other transporters, ENaC inhibition induced stronger natriuresis and diuresis in male rats than female rats. Overall, model predictions agreed well with measured changes in Na(+) and K(+) excretion in response to diuretics and Na(+) transporter mutations.

Background Increased nerve activity causes hypertension and kidney disease. Recent studies suggest that renal denervation reduces BP in patients with hypertension. Renal NE release is regulated by prejunctional α2A-adrenoceptors on sympathetic nerves, and α2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of α2A-adrenoceptors in the pathogenesis of hypertensive kidney disease is unknown. Methods We investigated effects of α2A-adrenoceptor-regulated renal NE release on the development of angiotensin II-dependent hypertension and kidney disease. In uninephrectomized wild-type and α2A-adrenoceptor-knockout mice, we induced hypertensive kidney disease by infusing AngII for 28 days. Results Urinary NE excretion and BP did not differ between normotensive α2A-adrenoceptor-knockout mice and wild-type mice at baseline. However, NE excretion increased during AngII treatment, with the knockout mice displaying NE levels that were significantly higher than those of wild-type mice. Accordingly, the α2A-adrenoceptor-knockout mice exhibited a systolic BP increase, which was about 40 mm Hg higher than that found in wild-type mice, and more extensive kidney damage. In isolated kidneys, AngII-enhanced renal nerve stimulation induced NE release and pressor responses to a greater extent in kidneys from α2A-adrenoceptor-knockout mice. Activation of specific sodium transporters accompanied the exaggerated hypertensive BP response in α2A-adrenoceptor-deficient kidneys. These effects depend on renal nerves, as demonstrated by reduced severity of AngII-mediated hypertension and improved kidney function observed in α2A-adrenoceptor-knockout mice after renal denervation. Conclusions Our findings reveal a protective role of prejunctional inhibitory α2A-adrenoceptors in pathophysiologic conditions with an activated renin-angiotensin system, such as hypertensive kidney disease, and support the concept of sympatholytic therapy as a treatment.

Background Recent evidence emphasizes the critical role of inflammation in the development of diabetic nephropathy. Angiotensin-converting enzyme (ACE) plays an active role in regulating the renal inflammatory response associated with diabetes. Studies have also shown that ACE has roles in inflammation and the immune response that are independent of angiotensin II. ACE’s two catalytically independent domains, the N- and C-domains, can process a variety of substrates other than angiotensin I. Methods To examine the relative contributions of each ACE domain to the sodium retentive state, renal inflammation, and renal injury associated with diabetic kidney disease, we used streptozotocin to induce diabetes in wild-type mice and in genetic mouse models lacking either a functional ACE N-domain (NKO mice) or C-domain (CKO mice). Results In response to a saline challenge, diabetic NKO mice excreted 32% more urinary sodium compared with diabetic wild-type or CKO mice. Diabetic NKO mice also exhibited 55% less renal epithelial sodium channel cleavage (a marker of channel activity), 55% less renal IL-1 β , 53% less renal TNF- α , and 53% less albuminuria than diabetic wild-type mice. This protective phenotype was not associated with changes in renal angiotensin II levels. Further, we present evidence that the anti-inflammatory tetrapeptide N-acetyl-seryl-asparyl-lysyl-proline (AcSDKP), an ACE N-domain–specific substrate that accumulates in the urine of NKO mice, mediates the beneficial effects observed in the NKO. Conclusions These data indicate that increasing AcSDKP by blocking the ACE N-domain facilitates sodium excretion and ameliorates diabetic kidney disease independent of intrarenal angiotensin II regulation.

Background/Aims: Patients with cystic fibrosis (CF) are prone to the development of metabolic alkalosis; however, the pathogenesis of this life threatening derangement remains unknown. We hypothesized that altered acid base transport machinery in the kidney collecting duct underlies the mechanism of impaired bicarbonate elimination in the CF kidney. Methods: Balance studies in metabolic cages were performed in WT and CFTR knockout (CF) mice with the intestinal rescue in response to bicarbonate loading or salt restriction, and the expression levels and cellular distribution of acid base and electrolyte transporters in the proximal tubule, collecting duct and small intestine were examined by western blots, northern blots and/or immunofluorescence labeling. Results: Baseline parameters, including acid-base and systemic vascular volume status were comparable in WT and CF mice, as determined by blood gas, kidney renin expression and urine chloride excretion. Compared with WT animals, CF mice demonstrated a significantly higher serum HCO3- concentration (22.63 in WT vs. 26.83 mEq/l in CF mice; n=4, p=0.013) and serum pH (7.33 in WT vs. 7.42 in CF mice; n=4, p=0.00792) and exhibited impaired kidney HCO3- excretion (urine pH 8.10 in WT vs. 7.35 in CF mice; n=7, p=0.00990) following a 3-day oral bicarbonate load. When subjected to salt restriction, CF mice developed a significantly higher serum HCO3- concentration vs. WT animals (29.26 mEq/L in CF mice vs. 26.72 in WT; n=5, p=0.0291). Immunofluorescence labeling demonstrated a profound reduction in the apical expression of the Cl-/HCO3- exchanger pendrin in cortical collecting duct cells and western and northern blots indicated diminished plasma membrane abundance and mRNA expression of pendrin in CF kidneys. Conclusions: We propose that patients with cystic fibrosis are prone to the development of metabolic alkalosis secondary to the inactivation of the bicarbonate secreting transporter pendrin, specifically during volume depletion, which is a common occurrence in CF patients.

The World Health Organization ranks hypertension the leading global risk factor for disease, specifically, cardiovascular disease. Blood pressure (BP) is higher in Westernized populations consuming Na+-rich processed foods than in isolated societies consuming K+-rich natural foods. Evidence suggests that lowering dietary Na+ is particularly beneficial in hypertensive individuals who consume a high-Na+ diet. Nonetheless, numerous population studies demonstrate a relationship between higher dietary K+, estimated from urinary excretion or dietary recall, and lower BP, regardless of Na+ intake. Interventional studies with K+ supplementation suggest that it provides a direct benefit; K+ may also be a marker for other beneficial components of a “natural” diet. Recent studies in rodent models indicate mechanisms for the K+ benefit: the distal tubule Na+-Cl− cotransporter (NCC) controls Na+ delivery downstream to the collecting duct, where Na+ reabsorbed by epithelial Na+ channels drives K+ secretion and excretion through K+ channels in the same region. High dietary K+ provokes a decrease in NCC activity to drive more K+ secretion (and Na+ excretion, analogous to the actions of a thiazide diuretic) whether Na+ intake is high or low; low dietary K+ provokes an increase in NCC activity and Na+ retention, also independent of dietary Na+. Together, the findings suggest that public health efforts directed toward increasing consumption of K+-rich natural foods would reduce BP and, thus, cardiovascular and kidney disease.

Collectrin, encoded by the Tmem27 gene, is a transmembrane glycoprotein with approximately 50% homology with angiotensin converting enzyme 2, but without a catalytic domain. Collectrin is most abundantly expressed in the kidney proximal tubule and collecting duct epithelia, where it has an important role in amino acid transport. Collectrin is also expressed in endothelial cells throughout the vasculature, where it regulates L-arginine uptake. We previously reported that global deletion of collectrin leads to endothelial dysfunction, augmented salt sensitivity, and hypertension. Here, we performed kidney crosstransplants between wild-type (WT) and collectrin knockout (Tmem27Y/- ) mice to delineate the specific contribution of renal versus extrarenal collectrin on BP regulation and salt sensitivity. On a high-salt diet, WT mice with Tmem27Y/- kidneys had the highest systolic BP and were the only group to exhibit glomerular mesangial hypercellularity. Additional studies showed that, on a high-salt diet, Tmem27Y/- mice had lower renal blood flow, higher abundance of renal sodium-hydrogen antiporter 3, and lower lithium clearance than WT mice. In WT mice, administration of angiotensin II for 2 weeks downregulated collectrin expression in a type 1 angiotensin II receptor-dependent manner. This downregulation coincided with the onset of hypertension, such that WT and Tmem27Y/- mice had similar levels of hypertension after 2 weeks of angiotensin II administration. Altogether, these data suggest that salt sensitivity is determined by intrarenal collectrin, and increasing the abundance or activity of collectrin may have therapeutic benefits in the treatment of hypertension and salt sensitivity.

The goal of the present study was to investigate the functional implications of sexual dimorphism in the pattern of transporters along the rodent nephron as reported by Veiras et al. ( J Am Soc Nephrol 28: 3504–3517, 2017). To do so, we developed sex-specific computational models of water and solute transport along the superficial nephrons from male and female rat kidneys. The models account for the sex differences in the abundance of apical and basolateral transporters, single nephron glomerular filtration rate, and tubular dimensions. Model simulations predict that ~70% and 60% of filtered Na+ is reabsorbed by the proximal tubule of male and female rat kidneys, respectively. The lower fractional Na+ reabsorption in female kidneys is due primarily to their smaller transport area, lower Na+/H+ exchanger activity, and lower claudin-2 abundance, culminating in significantly larger fractional delivery of water and Na+ to the downstream nephron segments in female kidneys. Conversely, the female distal nephron exhibits a higher abundance of key Na+ transporters, including Na+-K+-Cl− cotransporters, Na+-Cl− cotransporters, and epithelial Na+ channels. The higher abundance of transporters accounts for the enhanced water and Na+ transport along the female, relative to male, distal nephron, resulting in similar urine excretion between the sexes. Consequently, in response to a saline load, the Na+ load delivered distally is greater in female rats than male rats, overwhelming transport capacity and resulting in higher natriuresis in female rats.

When chronic kidney disease progresses to end stage renal disease, the optimal treatment is living kidney donation (LKD). A 10 yr prospective study of 1214 donors (PMID 27006347), reported that LKD increased risk of hypertension (HTN), by 3.64-fold, as well as HTN induced albuminuria. Our objective was to test whether a DASH-style diet (DD: 0.74% NaCl, 3%K with 1% each: Cl - , citrate, HCO 3 - ) would blunt hypertension and albuminuria following UNX vs. a western style diet (WD: 2% NaCl, 1%KCl). Uninephrectomized (UNX) male SD rats (n=5/group) preequilibrated on diets were analyzed 12-14 wks post-UNX. Systolic BP (SBP, mmHg) was similar pre-UNX in DD (126 ± 8) and WD (132 ± 8); SBP increased post-UNX by 7 ± 2 (DD) and 21 ± 5 (WD) mmHg, p=0.04. Urine injury markers (albumin, angiotensinogen, KIM-1 and plasminogen) increased in both DD and WD (all p Transporter profiles were generated from both pre-and post-UNX kidneys. Pre-UNX, DD (vs. WD) exhibited lower abundance of proximal tubule (PT) NHE3, NaPi2 and NHERF1, and higher abundance of NKA α1, NCC, NCCp, claudin 7, SPAK, ENaC subunits and AQP2 (all p < 0.01). Post-UNX (vs. pre-UNX) abundance, normalized to equivalent protein, exhibited lower claudin2, megalin, AQP1 and AQP2 in both DD and WD (all p < 0.01), and, specifically to DD post-UNX: 1.4-fold increases in NCCp, SPAKp and 0.7-fold decreases in cleaved α and γ ENaC (all p In conclusion, the phenotype of HTN and proteinuria observed following LKD in humans is evident in this pilot SD rat study. Compared to the 2% NaCl/1% KCl “Western style” diet, the 3% K + and alkali rich “DASH style diet” lowered baseline PT transporter levels, increased CLi (indicator of flow out of PT), elevated distal Na + transporters (likely due to flow from PT) and blunted the rise in BP post-UNX. The findings suggest that DASH style dietary electrolytes may improve outcomes following LKD.

Introduction: Diabetic nephropathy is characterized by renal inflammation and impaired kidney function that predisposes to salt-sensitive hypertension. However, the prevalence of diabetic kidney disease is lower in females compared to males. Here, we aim to study the sexual differences associated with the progression of diabetic nephropathy and the response to a high salt diet. Methods: Four- and seven-month old male and female diabetic (db/db) and non-diabetic (db/+) mice received either a high-salt (4% NaCl w/w) or a control (0.4% NaCl w/w) diet for four weeks (n=4). Mean arterial pressure (MAP) was measured by telemetry. To evaluate sodium handling, mice were challenged with an intraperitoneal injection of saline solution (0.9% NaCl) in a volume equivalent to 10% of the mouse body weight and hourly sodium excretion was evaluated by flame photometry. Finally, mice were euthanized, and kidneys were preserved to assess renal inflammation. Results: At 4 months, a high salt diet did not modify blood pressure in any experimental group. However, male diabetic mice showed higher abundance of renal TNFα (1.8-fold increase, P P P P P P Conclusion: Even in the absence of salt sensitivity, 4-month old diabetic males display renal inflammation and sodium retention. This is associated with the development of salt-sensitive hypertension at 7 months. Diabetic female mice are protected against the progression of diabetic nephropathy and do not develop salt sensitivity.

Summary The kidneys maintain homeostasis by controlling the amount of water and electrolytes in the blood. That function is accomplished by the nephrons, which transform glomerular filtrate into urine by a transport process mediated by membrane transporters. We postulate that the distribution of renal transporters along the nephron is markedly different between men and women, as recently shown in rodents. We hypothesize that the larger abundance of a renal Na+ transport in the proximal tubules in females may also better prepare them for the fluid retention adaptations required during pregnancy and lactation. Also, kidneys play a key role in blood pressure regulation, and a popular class of anti-hypertensive medications and angiotensin converting enzymes (ACE) inhibitors have been reported to be less effective in women. Model simulations suggest that the blunted natriuretic and diuretic effects of ACE inhibition in women can be attributed, in part, to their higher distal baseline transport capacity., Graphical abstract, Highlights • We have developed sex-specific models of solute and water transport in human kidneys • Human kidneys likely exhibit sexually dimorphic membrane transporter distribution • The pattern may prepare women for fluid retention required in pregnancy and lactation • The pattern may explain the lesser efficacy of ACE inhibitors in hypertensive women, Human Physiology; Bioinformatics; Mathematical biosciences

Angiotensin II (AngII) hypertension increases distal tubule Na-Cl cotransporter (NCC) abundance and phosphorylation (NCCp), as well as epithelial Na + channel abundance and activating cleavage. Acutely raising plasma [K + ] by infusion or ingestion provokes a rapid decrease in NCCp that drives a compensatory kaliuresis. The first aim tested whether acutely raising plasma [K + ] with a single 3-hour 2% potassium meal would lower NCCp in Sprague–Dawley rats after 14 days of AngII (400 ng/kg per minute). The potassium-rich meal neither decreased NCCp nor increased K + excretion. AngII-infused rats exhibited lower plasma [K + ] versus controls (3.6±0.2 versus 4.5±0.1 mmol/L; P + channel activation provokes K + depletion. The second aim tested whether doubling dietary potassium intake from 1% (A1K) to 2% (A2K) would prevent K + depletion during AngII infusion and, thus, prevent NCC accumulation. A2K-fed rats exhibited normal plasma [K + ] and 2-fold higher K + excretion and plasma [aldosterone] versus A1K. In A1K rats, NCC, NCCpS71, and NCCpT53 abundance increased 1.5- to 3-fold versus controls ( P + channel subunit abundance and cleavage increased 1.5- to 3-fold in both A1K and A2K; ROMK (renal outer medulla K + channel abundance) abundance was unaffected by AngII or dietary K + . In summary, the accumulation and phosphorylation of NCC seen during chronic AngII infusion hypertension is likely secondary to potassium deficiency driven by epithelial Na + channel stimulation.

Angiotensin-converting enzyme (ACE) plays a key role in renal inflammation and sodium retention associated with diabetic nephropathy. Although most effects of ACE have been classically related to angiotensin (Ang) II synthesis, studies highlight an Ang II-independent role of ACE in inflammation. Indeed, ACE has two catalytic domains, the N- and C-domains, that can process a wide diversity of substrates besides Ang I. Here, we study the relative contributions of ACE domains to renal inflammation and sodium retention during diabetic nephropathy. Diabetes was induced with streptozotocin in wild-type (WT) mice and mice lacking either a functional ACE N-domain (NKO) or C-domain (CKO) (n=5-8). After 6 months of diabetes, we evaluated the natriuretic response to volume expansion. For this, mice were injected with 0.9% NaCl equivalent to 10% of their body weight. After 5 hours, diabetic NKO mice excreted 30% more urinary sodium in response to the saline challenge compared to diabetic WT or CKO mice ( P P P P P P P =NS). We next evaluated whether the anti-inflammatory tetrapeptide N-acetyl-seryl-asparyl-lysyl-proline (AcSDKP), an ACE N-domain specific substrate, mediates the protective phenotype of NKO. For this, diabetic mice were treated with the prolyl oligopeptidase inhibitor, S17092 (10 mg/kg, IP), that prevents the synthesis of AcSDKP. In diabetic NKO mice receiving S17092, sodium excretion in response to a saline challenge, ENaC α and γ subunit cleavage, renal inflammation and renal injury were indistinguishable from equally treated diabetic WT mice. In summary, these data indicate that increasing AcSDKP by blocking the ACE N-domain improves sodium handling and ameliorates diabetic kidney disease independently of intrarenal Ang II regulation.

Salt-sensitivity is present in 50% of all hypertensive individuals. Prior studies have focused on the roles of kidney, vasculature and sympathetic activity in salt-sensitivity but the contribution of immune cells is poorly understood. We recently found that in murine dendritic cells amiloride sensitive channels sense salt and trigger NADPH oxidase-dependent formation of isolevuglandin-(IsolG)-adducts. We tested the hypothesis that human monocytes exhibit salt-sensitivity leading to activation via IsoLG-adduct formation and this is associated with cardiovascular risk factors. In a cohort of 18 subjects, we found that the sodium intake, measured by 24 hours urine excretion (UNa) was positively correlated with plasma levels of IsolGs. We also measured accumulation of interstitial sodium in 70 subjects by Magnetic Sodium Resonance and evaluated their circulating monocytes by flow cytometry. Subjects with high skin sodium had higher levels of IsoLGs in their monocytes (24±6 vs 38±6 %, pp =0.04). To investigate the ability of monocytes to respond to salt, we cultured monocytes from 17 subjects in high salt environment (HS:190 mM NaCl) or normal media (NS:150mM NaCl) for 48 hours. In culture, 47% of the subjects respond to salt, denoted by an increase of at least 20% in IsoLG formation (NS: 1327±240 vs. HS: 2217±653, p =0.009) as well as increased expression of the activation markers CD83 and CD86. The subjects’ cardiovascular risk factors including pulse pressure, BMI, glucose and total cholesterol positively correlated with the amount of IsolGs produced (ΔHS-NS) in response to salt (r=0.51 p

The goal of this study is to investigate the functional implications of the sexual dimorphism in transporter patterns along the proximal tubule. To do so, we have developed sex-specific computational models of solute and water transport in the proximal convoluted tubule of the rat kidney. The models account for the sex differences in expression levels of the apical and basolateral transporters, in single-nephron glomerular filtration rate, and in tubular dimensions. Model simulations predict that 70.6 and 38.7% of the filtered volume is reabsorbed by the proximal tubule of the male and female rat kidneys, respectively. The lower fractional volume reabsorption in females can be attributed to their smaller transport area and lower aquaporin-1 expression level. The latter also results in a larger contribution of the paracellular pathway to water transport. Correspondingly similar fractions (70.9 and 39.2%) of the filtered Na+ are reabsorbed by the male and female proximal tubule models, respectively. The lower fractional Na+ reabsorption in females is due primarily to their smaller transport area and lower Na+/H+ exchanger isoform 3 and claudin-2 expression levels. Notably, unlike most Na+ transporters, whose expression levels are lower in females, Na+-glucose cotransporter 2 (SGLT2) expression levels are 2.5-fold higher in females. Model simulations suggest that the higher SGLT2 expression in females may compensate for their lower tubular transport area to achieve a hyperglycemic tolerance similar to that of males.

Hypertension is the leading cause of stroke and cardiovascular diseases and a leading risk factor for global disease burden, affecting 30% of the adult population in Western cultures.1 Blood pressure (BP) can be elevated by vasoconstriction and by increasing the circulating volume. Evidence from studies of mutations in renal Na+ transporters, renal transplantation, and diuretic action supports Guyton’s hypothesis that long-term regulation of effective circulating volume and BP depends on fractional renal Na+ reabsorption.2–4 Ultimately, excess Na+ reabsorption (Figure, red arrows) raises effective circulating volume and BP which provoke counteracting natriuretic responses to match Na+ output to Na+ intake at the expense of elevated BP (Figure, blue arrow).2 We and others have determined that pressure natriuresis responses involve Na+ transporter inhibition at multiple levels of regulation.5–13 According to Guyton, kidneys possess the capacity to excrete enough Na+ and volume to normalize BP in the face of expanded effective circulating volume.2 Thus, hypertension can be characterized as a failure of compensatory renal pressure natriuresis. Indeed, there is strong evidence that the pressure natriuresis response is impaired during experimental hypertension by inflammation, immune cell infiltration, and intrarenal angiotensin II (AngII) production, secondary to initiating stimuli such as AngII infusion, reduced NO production, high-salt diet, or elevated renal sympathetic nerve activity.14–17 This brief review focuses on the natriuretic effectors and addresses (1) the renal tubular locations and transporters that participate in pressure natriuresis and (2) the mechanisms that blunt the response in experimental models of hypertension. Figure. Renal transporter profile reveals region specific transporter regulation during experimental hypertension. A , Anatomic arrangement of renal cortex and renal medulla in a kidney cross-section …

Pregnancy is characterized by plasma volume expansion due to Na+ retention, driven by aldosterone. The aldosterone-responsive epithelial Na+ channel is activated in the kidney in pregnancy. In the present study, we investigated the aldosterone-responsive Na+-Cl− cotransporter (NCC) in mid- and late pregnant rats compared with virgin rats. We determined the abundance of total NCC, phosphorylated NCC (pNCC; pT53, pS71 and pS89), phosphorylated STE20/SPS-1-related proline-alanine-rich protein kinase (pSPAK; pS373), and phosphorylated oxidative stress-related kinase (pOSR1; pS325) in the kidney cortex. We also measured mRNA expression of NCC and members of the SPAK/NCC regulatory kinase network, serum and glucocorticoid-regulated kinase (SGK)1, total with no lysine kinase (WNK)1, WNK3, and WNK4. Additionally, we performed immunohistochemistry for NCC kidneys from virgin and pregnant rats. Total NCC, pNCC, and pSPAK/OSR1 abundance were unchanged in midpregnant versus virgin rats. In late pregnant versus virgin rats, total NCC and pNCC were decreased; however, pSPAK/OSR1 was unchanged. We detected no differences in mRNA expression of NCC, SGK1, total WNK1, WNK3, and WNK4. By immunohistochemistry, NCC was mainly localized to the apical region in virgin rats, and density in the apical region was reduced in late pregnancy. Therefore, despite high circulating aldosterone levels in pregnancy, the aldosterone-responsive transporter NCC is not increased in total or activated (phosphorylated) abundance or in apical localization in midpregnant rats, and all are reduced in late pregnancy. This contrasts to the mineralocorticoid-mediated activation of the epithelial Na+ channel, which we have previously reported. Why and how NCC escapes aldosterone activation in pregnancy is not clear but may relate to regional differences in aldosterone sensitivity the increased K+ intake or other undefined mechanisms.