Sustained inhibition of ENaC in CF: Potential RNA-based therapies for mutation-agnostic treatment.

Disruption of the equilibrium between ion secretion and absorption processes by the airway epithelium is central to many muco-obstructive lung diseases including cystic fibrosis (CF). Besides correction of defective folding and function of CFTR, inhibition of amiloride-sensitive epithelia sodium channels (ENaC) has emerged as a bona fide therapeutic strategy to improve mucociliary clearance in patients with CF. The short half-life of amiloride-based ENaC blockers and hyperosmotic therapies have led to the development of novel RNA-based interventions for targeted and sustained reduction of ENaC expression and function in preclinical models of CF. This review summarizes the recent advances in RNA therapeutics targeting ENaC for mutation-agnostic treatment of CF.

Plasminogen Deficiency and Amiloride Mitigate Angiotensin II-Induced Hypertension in Type 1 Diabetic Mice Suggesting Effects Through the Epithelial Sodium Channel.

Background Diabetic nephropathy is a common diabetes mellitus complication associated with hypertension, proteinuria, and excretion of urinary plasmin that activates the epithelial sodium channel, ENaC, in vitro. Here we hypothesized that the deletion of plasminogen and amiloride treatment protect against hypertension in diabetes mellitus. Methods and Results Male plasminogen knockout (plasminogen-deficient [Plg-/-]) and wild-type mice were rendered diabetic with streptozotocin. Arterial blood pressure was recorded continuously by indwelling catheters before and during 10 days of angiotensin II infusion (ANGII; 30-60 ng/kg per minute). The effect of amiloride infusion (2 mg/kg per day, 4 days) was tested in wild-type, diabetic ANGII-treated mice. Streptozotocin increased plasma and urine glucose concentrations and 24-hour urine albumin and plasminogen excretion. Diabetic Plg-/- mice displayed larger baseline albuminuria and absence of urine plasminogen. Baseline mean arterial blood pressure did not differ between groups. Although ANGII elevated blood pressure in wild-type, diabetic wild-type, and Plg-/- control mice, ANGII did not change blood pressure in diabetic Plg-/- mice. Compared with ANGII infusion alone, wild-type ANGII-infused diabetic mice showed blood pressure reduction upon amiloride treatment. There was no difference in plasma renin, ANGII, aldosterone, tissue prorenin receptor, renal inflammation, and fibrosis between groups. Urine from wild-type mice evoked larger amiloride-sensitive current than urine from Plg-/- mice with or without diabetes mellitus. Full-length γ-ENaC and α-ENaC subunit abundances were not changed in kidney homogenates, but the 70 kDa γ-ENaC cleavage product was increased in diabetic versus nondiabetic mice. Conclusions Plasmin promotes hypertension in diabetes mellitus with albuminuria likely through the epithelial sodium channel.

Rational use of mucoactive medications to treat pediatric airway disease.

Many airway diseases in children, notably bronchiolitis, cystic fibrosis (CF), non-CF bronchiectasis including primary ciliary dyskinesia, pneumonia, and severe asthma are associated with retention of airway secretions. Medications to improve secretions clearance, the mucoactive medications, are employed to treat these diseases with varying degrees of success. This manuscript reviews evidence for the use of these medications and future directions of study.

Cystic Fibrosis: Emergence of Highly Effective Targeted Therapeutics and Potential Clinical Implications.

Cystic fibrosis (CF) remains the most common life-shortening hereditary disease in white populations, with high morbidity and mortality related to chronic airway mucus obstruction, inflammation, infection, and progressive lung damage. In 1989, the discovery that CF is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene that encodes a cAMP-dependent anion channel vital for proper Cl- and HCO3- transport across epithelial surfaces provided a solid foundation for unraveling underlying disease mechanisms and the development of therapeutics targeting the basic defect in people with CF. In this review, we focus on recent advances in our understanding of the molecular defects caused by different classes of CFTR mutations, implications for pharmacological rescue of mutant CFTR, and insights into how CFTR dysfunction impairs key host defense mechanisms, such as mucociliary clearance and bacterial killing in CF airways. Furthermore, we review the path that led to the recent breakthrough in the development of highly effective CFTR-directed therapeutics, now applicable for up to 90% of people with CF who carry responsive CFTR mutations, including those with just a single copy of the most common F508del mutation. Finally, we discuss the remaining challenges and strategies to develop highly effective targeted therapies for all patients and the unprecedented potential of these novel therapies to transform CF from a fatal to a treatable chronic condition.

Registration of amiloride in South Africa: Cutting the Gordian knot.

Amiloride is an antagonist of the renal tubular epithelial sodium channel (ENaC). As such, it is a diuretic that is both potassium and magnesium sparing. It is used for the treatment of potassium depletion and hypertension, and is the specific therapy for hypertension due to overactivity of the ENaC (Liddle syndrome and several additional genetic causes of the Liddle phenotype - low renin and low aldosterone). It is listed as a World Health Organization essential drug, but has never been registered in South Africa (SA) and can therefore only be prescribed under a Section 21 application to the SA Health Products Regulatory Authority (SAHPRA) on a case-by-case basis. In SA, >50% of patients treated for hypertension are not controlled. In the USA, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study reported that African Americans are more likely to be diagnosed with hypertension, more likely to be treated, more likely to be treated intensively, and less likely to achieve blood pressure (BP) control. Although the reasons are complex, studies show that 10 - 20% of blacks may carry the Liddle phenotype. Observational data and a controlled clinical trial done in three African countries have shown that these patients respond to amiloride and not to conventional guideline-based antihypertensive treatment. The former is likely to result in a significant reduction in cardiovascular, stroke and kidney morbidity and mortality, because of improved BP control. Amiloride is very unlikely to ever be registered in SA, as it was first developed >50 years ago, and SAHPRA regulations prevent widespread prescription of this essential drug. This is a classic Gordian knot that requires a novel approach from authorities to sever the knot and improve the health of many South Africans.

Liddle syndrome due to a novel mutation in the γ subunit of the epithelial sodium channel (ENaC) in family from Russia: a case report.

BACKGROUND: Liddle syndrome is a monogenic disease with autosomal dominant inheritance. Basic characteristics of this disease are hypertension, reduced concentration of aldosterone and renin activity, as well as increased excretion of potassium leading to low level of potassium in serum and metabolic alkalosis. The cause of Liddle syndrome is missense or frameshift mutations in SCNN1A, SCNN1B, or SCNN1G genes that encode epithelial sodium channel subunits. CASE PRESENTATION: We describe a family with Liddle syndrome from Russia. 15-year-old proband has arterial hypertension, hypokalemia, hyporeninemia, metabolic alkalosis, but aldosterone level is within the normal range. At 12 years of age, arterial hypertension was noticed for the first time. We identified novel frameshift mutation c.1769delG (p.Gly590Alafs) in SCNN1G, which encodes the γ subunit of ENaC in vertebrates. The father and younger sister also harbor this heterozygous deletion. Treatment with amiloride of proband and his sister did not normalize the blood pressure, but normalized level of plasma renin activity. CONCLUSIONS: Our results expand the mutational spectrum of Liddle syndrome and provide further proof that the conserved PY motif is crucial to control of ENaC activity. Genetic analysis has implications for the management of hypertension, specific treatment with amiloride and counselling in families with Liddle syndrome.

First clinical trials of novel ENaC targeting therapy, SPX-101, in healthy volunteers and adults with cystic fibrosis.

BACKGROUND: ENaC inhibition has been investigated as a CF treatment; however, small molecule inhibitors of ENaC lack efficacy and/or have shown dose-limiting hyperkalemia. SPX-101 is a novel, investigational small peptide (SPLUNC1 mimetic) that regulates ENaC density with the potential for efficacy without systemic effects. METHODS: Two trials are presented: The first was a Phase 1, 2-part, randomized, double-blind, placebo-controlled, ascending-dose study of nebulized SPX-101 in healthy adults. Part 1 evaluated 4 single doses of SPX-101 ranging from 20 to 240 mg. Part 2 evaluated a 14-day regimen of SPX-101 at 4 doses of SPX-101 ranging from 10 to 120 mg BID. Pharmacokinetics, adverse events, spirometry, vital signs, electrocardiograms, pulse oximetry, and clinical laboratory values were assessed. The second trial was a tolerability-confirming, Phase 1b, open-label study conducted in 5 adult subjects with CF. Ascending doses of SPX-101 inhalation solution (10 mg-120 mg BID) were administered for 7 days. Safety was assessed as described above. RESULTS: All 64 healthy volunteers (32 in each Part) completed the single and multiple dose study. SPX-101 was well tolerated with little/no systemic exposure and with no hyperkalemia. Adverse events were generally mild with reported respiratory events associated with the purported pharmacological activity of SPX-101. Tolerability of SPX-101 was similarly observed in adults with CF; all 5 subjects treated with SPX-101 completed the study. CONCLUSIONS: SPX-101 was well-tolerated across a range of doses and had little/no systemic exposure in healthy adults and adults with CF, thus supporting further study in patients with CF. CLINICALTRIAL. GOV REGISTRATION: NCT03056989.

Maintenance of long-term blood pressure control and vascular health by low-dose amiloride-based therapy in hyperaldosteronism.

Whether aldosterone itself contributes directly to macro- or microcirculatory disease in man or to adverse cardiovascular outcomes is not fully known. We report our long-term single-practice experience in an unusual group of five patients with chronic hyperaldosteronism (HA, including three with glucocorticoid-remediable aldosteronism, GRA) treated with low-dose amiloride (a specific epithelial sodium channel [ENaC] blocker) 5-10 (mean 7) mg daily for 14-28 (mean 20) years. Except for one GRA diagnosed in infancy, all had severe resistant hypertension. In each case, BP was normalized within 1-4 weeks after starting amiloride and office BP's remained well controlled throughout the next two decades. 24-hour ambulatory BP monitoring with pulse wave analysis (cardiac output, vascular resistance, augmentation index, reflection magnitude), regional pulse wave velocities, pulse stiffening ratio, ankle-brachial index, serum creatinine, estimated glomerular filtration rate, and spot urinary albumin:creatinine ratio were measured after a mean of 18 years; all of these indicators were essentially normal. Over two additional years of observation (100 patient-years total), no cardiovascular or renal event occurred. We conclude that long-term ENaC blockade with amiloride can normalize BP and protect macro- and microvascular function in patients with HA. This suggests that either (a) putative vasculopathic effects of aldosterone are mediated via ENaC or (b) aldosterone may not play a direct role in age-dependent vasculopathic changes in humans independent of blood pressure. These findings, coupled with our literature review in both animal and human results, underscore the need for additional studies.

Lovastatin attenuates hypertension induced by renal tubule-specific knockout of ATP-binding cassette transporter A1, by inhibiting epithelial sodium channels.

BACKGROUND AND PURPOSE: We have shown that cholesterol is synthesized in the principal cells of renal cortical collecting ducts (CCD) and stimulates the epithelial sodium channels (ENaC). Here we have determined whether lovastatin, a cholesterol synthesis inhibitor, can antagonize the hypertension induced by activated ENaC, following deletion of the cholesterol transporter (ATP-binding cassette transporter A1; ABCA1). EXPERIMENTAL APPROACH: We selectively deleted ABCA1 in the principal cells of mouse CCD and used the cell-attached patch-clamp technique to record ENaC activity. Western blot and immunofluorescence staining were used to evaluate protein expression levels. Systolic BP was measured with the tail-cuff method. KEY RESULTS: Specific deletion of ABCA1 elevated BP and ENaC single-channel activity in the principal cells of CCD in mice. These effects were antagonized by lovastatin. ABCA1 deletion elevated intracellular cholesterol levels, which was accompanied by elevated ROS, increased expression of serum/glucocorticoid regulated kinase 1 (Sgk1), phosphorylated neural precursor cell-expressed developmentally down-regulated protein 4-2 (Nedd4-2) and furin, along with shorten the primary cilium, and reduced ATP levels in urine. CONCLUSIONS AND IMPLICATIONS: These data suggest that specific deletion of ABCA1 in principal cells increases BP by stimulating ENaC channels via a cholesterol-dependent pathway which induces several secondary responses associated with oxidative stress, activated Sgk1/Nedd4-2, increased furin expression, and reduced cilium-mediated release of ATP. As ABCA1 can be blocked by cyclosporine A, these results suggest further investigation of the possible use of statins to treat CsA-induced hypertension.

Epithelial sodium channel blockade and new ß-ENaC polymorphisms among normotensive and hypertensive adult Nigerians.

We sought to determine the effect of amiloride on blood pressure (BP) and the presence of polymorphisms of the ß-subunit of the epithelial sodium channel (ENaC) among normotensive (NT) and hypertensive (HT) Nigerians. Healthy volunteers-47 NT and 53 age-matched HT were recruited after giving informed consent. Subjects were salt-loaded with 200 mmol of NaCl daily for 5 days. Following a week washout period, salt-loading was repeated in addition to the administration of 5 mg amiloride daily for five days. Blood pressure, plasma and urine electrolytes were measured at baseline, after salt-loading and after salt-loading plus amiloride. PCR amplicons were sequenced for ß-ENaC polymorphisms. Salt-loading led to a significant increase (p < 0.05) in SBP among NT and HT and in DBP (p < 0.001) only among HT. Amiloride reduced SBP and DBP to below baseline levels in NT (p < 0.05) and HT (p < 0.001) subjects. Five of the subjects had the ß-T594M polymorphism, HT 3/53; NT 2/47 (p = 0.75). Four previously unreported ß-ENaC mutations were recorded: E632V and E636V, respectively, among two HT subjects, D638Y in another HT and L628Q in one NT subject. We showed the presence of ß-ENaC polymorphisms among our populace and the possible usefulness of amiloride as a single antihypertensive among Nigerians.

The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis.

Cystic fibrosis (CF) is a monogenic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR dysfunction is characterized by abnormal mucociliary transport due to a dehydrated airway surface liquid (ASL) and hyperviscous mucus, among other pathologies of host defense. ASL depletion is caused by the absence of CFTR mediated chloride secretion along with continued activity of the epithelial sodium channel (ENaC) activity, which can also be affected by CFTR mediated anion conductance. Therefore, ENaC has been proposed as a therapeutic target to ameliorate ASL dehydration and improve mucus transport. Inhibition of ENaC has been shown to restore ASL hydration and enhance mucociliary transport in induced models of CF lung disease. To date, no therapy inhibiting ENaC has successfully translated to clinical efficacy, in part due to concerns regarding off-target effects, systemic exposure, durability of effect, and adverse effects. Recent efforts have been made to develop novel, rationally designed therapeutics to produce-specific, long-lasting inhibition of ENaC activity in the airways while simultaneously minimizing off target fluid transport effects, systemic exposure and side effects. Such approaches comprise next-generation small molecule direct inhibitors, indirect channel-activating protease inhibitors, synthetic peptide analogs, and oligonucleotide-based therapies. These novel therapeutics represent an exciting step forward in the development of ENaC-directed therapies for CF.

Amiloride resolves resistant edema and hypertension in a patient with nephrotic syndrome; a case report.

Sodium and fluid retention is a hallmark and a therapeutic challenge of the nephrotic syndrome (NS). Studies support the "overfill" theory of NS with pathophysiological proteolytic activation of the epithelial sodium channel (ENaC) which explains the common observation of suppressed renin -angiotensin system and poor therapeutic response to ACE inhibitors. Blockade of ENaC by the diuretic amiloride would be a rational intervention compared to the traditionally used loop diuretics. We describe a 38-year-old male patient with type1 diabetes who developed severe hypertension (200/140 mmHg), progressive edema (of at least 10 L), and overt proteinuria (18.5 g/24 h), despite combined administration of five antihypertensive drugs. Addition of amiloride (5 mg/day) to treatment resulted in resolution of edema, weight loss of 7 kg, reduction in blood pressure (150/100-125/81 mmHg), increased 24 h urinary sodium excretion (127-165 mmol/day), decreased eGFR (41-29 mL/min), and increased plasma potassium concentration (4.6-7.8 mmol/L). Blocking of ENaC mobilizes nephrotic edema and lowers blood pressure in NS. However, acute kidney injury and dangerous hyperkalemia is a potential risk if amiloride is added to multiple other antihypertensive medications as ACEi and spironolactone. The findings support that ENaC is active in NS and is a relevant target in adult NS patients.

Diagnosis and management of resistant hypertension: state of the art.

Resistant hypertension is defined as a lack of ambulatory blood pressure response to optimized medical treatment after exclusion of secondary hypertension in patients who are fully adherent to antihypertensive therapy. Patients with resistant hypertension are at high risk of complications, particularly cardiovascular events, and optimization of medical treatment remains the cornerstone of their management. Such optimization should be based on simple algorithms and include the use of aldosterone antagonists. The available data from clinical trials do not support the use of device-based approaches such as renal denervation, baroreflex activation therapy or arteriovenous anastomosis for the treatment of resistant hypertension in the majority of patients. Therefore, device treatment remains a last-resort for patients with truly resistant hypertension in the context of clinical research in highly skilled tertiary referral centres. Future research should focus on improving understanding of the intrinsic (physiological and psychological factors) and extrinsic (environmental stressors) mechanisms that contribute to a lack of response to blood-pressure-lowering drugs in adherent patients. The use of biomarkers to identify patients with early target organ damage and new technologies, such as renal nerve stimulation, to predict blood pressure responses to renal denervation could aid the selection of patients who might benefit from device therapies.

SPX-101 Is a Novel Epithelial Sodium Channel-targeted Therapeutic for Cystic Fibrosis That Restores Mucus Transport.

RATIONALE: Cystic fibrosis (CF) lung disease is caused by the loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) combined with hyperactivation of the epithelial sodium channel (ENaC). In the lung, ENaC is responsible for movement of sodium. Hyperactivation of ENaC, which creates an osmotic gradient that pulls fluid out of the airway, contributes to reduced airway hydration, causing mucus dehydration, decreased mucociliary clearance, and recurrent acute bacterial infections. ENaC represents a therapeutic target to treat all patients with CF independent of their underlying CFTR mutation. OBJECTIVES: To investigate the in vitro and in vivo efficacy of SPX-101, a peptide mimetic of the natural regulation of ENaC activity by short palate, lung, and nasal epithelial clone 1, known as SPLUNC1. METHODS: ENaC internalization by SPX-101 in primary human bronchial epithelial cells from healthy and CF donors was assessed by surface biotinylation and subsequent Western blot analysis. SPX-101's in vivo therapeutic effect was assessed by survival of ß-ENaC-transgenic mice, mucus transport in these mice, and mucus transport in a sheep model of CF. MEASUREMENTS AND MAIN RESULTS: SPX-101 binds selectively to ENaC and promotes internalization of the α-, ß-, and γ-subunits. Removing ENaC from the membrane with SPX-101 causes a significant decrease in amiloride-sensitive current. The peptide increases survival of ß-ENaC-transgenic mice to greater than 90% with once-daily dosing by inhalation. SPX-101 increased mucus transport in the ß-ENaC mouse model as well as the sheep model of CF. CONCLUSIONS: These data demonstrate that SPX-101 promotes durable reduction of ENaC membrane concentration, leading to significant improvements in mucus transport.

Genetic causes of hypomagnesemia, a clinical overview.

Magnesium is essential to the proper functioning of numerous cellular processes. Magnesium ion (Mg2+) deficits, as reflected in hypomagnesemia, can cause neuromuscular irritability, seizures and cardiac arrhythmias. With normal Mg2+ intake, homeostasis is maintained primarily through the regulated reabsorption of Mg2+ by the thick ascending limb of Henle's loop and distal convoluted tubule of the kidney. Inadequate reabsorption results in renal Mg2+ wasting, as evidenced by an inappropriately high fractional Mg2+ excretion. Familial renal Mg2+ wasting is suggestive of a genetic cause, and subsequent studies in these hypomagnesemic families have revealed over a dozen genes directly or indirectly involved in Mg2+ transport. Those can be classified into four groups: hypercalciuric hypomagnesemias (encompassing mutations in CLDN16, CLDN19, CASR, CLCNKB), Gitelman-like hypomagnesemias (CLCNKB, SLC12A3, BSND, KCNJ10, FYXD2, HNF1B, PCBD1), mitochondrial hypomagnesemias (SARS2, MT-TI, Kearns-Sayre syndrome) and other hypomagnesemias (TRPM6, CNMM2, EGF, EGFR, KCNA1, FAM111A). Although identification of these genes has not yet changed treatment, which remains Mg2+ supplementation, it has contributed enormously to our understanding of Mg2+ transport and renal function. In this review, we discuss general mechanisms and symptoms of genetic causes of hypomagnesemia as well as the specific molecular mechanisms and clinical phenotypes associated with each syndrome.

Liddle syndrome: clinical and genetic profiles.

Liddle syndrome is a rare autosomal dominant monogenic form of hypertension. The authors analyzed clinical and genetic features of 12 cases of Liddle syndrome, the largest sample size ever reported. Clinical data were studied retrospectively. The exon 13 of the ß and γ subunits of the epithelial sodium channel were amplified and sequenced in the peripheral blood leukocytes of the patients. The onset age of the 12 patients was 15.5±3.3 years. Their blood pressures were poorly controlled, and serum potassium levels in most patients were <3.0 mmol/L. Upright plasma renin activity and plasma aldosterone concentration were suppressed in all patients. All patients were treated with triamterene, and blood pressures were well controlled and serum potassium levels returned to normal. The serum creatinine level rose to 124 and 161 µmol/L, respectively, in two patients upon triamterene treatment, and returned to normal soon after treatment was discontinued. Eight mutation alleles were identified, and three mutations were newly identified.

Proanthocyanidins block aldosterone-dependent up-regulation of cardiac gamma ENaC and Nedd4-2 inactivation via SGK1.

Aldosterone plays a central role in the development of cardiac pathological states involving ion transport imbalances, especially sodium transport. We have previously demonstrated a cardioprotective effect of proanthocyanidins in aldosterone-treated rats. Our objective was to investigate for the first time the effect of proanthocyanidins on serum and glucocorticoid-regulated kinase 1 (SGK1), epithelial Na+ channel (γ-ENaC), neuronal precursor cells expressed developmentally down-regulated 4-2 (Nedd4-2) and phosphoNedd4-2 protein expression in the hearts of aldosterone-treated rats. Male Wistar rats received aldosterone (1mg kg-1day-1)+1% NaCl for 3weeks. Half of the animals in each group were simultaneously treated with the proanthocyanidins-rich extract (80% w/w) (PRO80, 5mg kg-1day-1). Hypertension and diastolic dysfunction induced by aldosterone were abolished by treatment with PRO80. Expression of fibrotic, inflammatory and oxidative mediators were increased by aldosterone-salt administration and blunted by PRO80. Antioxidant capacity was improved by PRO80. The up-regulated aldosterone mediator SGK1, ENaC and p-Nedd4-2/total Nedd4-2 ratio were blocked by PRO80. PRO80 blunted aldosterone-mineralocorticoid-mediated up-regulation of ENaC provides new mechanistic insight of the beneficial effect of proanthocyanidins preventing the cardiac alterations induced by aldosterone excess.

Significant natriuretic and antihypertensive action of the epithelial sodium channel blocker amiloride in diabetic patients with and without nephropathy.

OBJECTIVE: Diabetic nephropathy is associated with aberrant glomerular filtration of serine proteases. The study was designed to test the hypothesis that the epithelial sodium channel is activated proteolytically by urine plasmin in diabetic nephropathy and mediates renal sodium retention. METHODS: In an open-label intervention study on type 1 diabetes patients on standardized NaCl intake (200 mmol/day) with (n = 15) and without diabetic nephropathy (control, n = 12), urinary Na excretion in response to oral amiloride (20 or 40 mg/day for 2 days) was compared. RESULTS: A total of 27 patients completed the study and nine diabetic nephropathy and eight control study participants were compliant (24-h urine Na excretion of 200 mmol ±â€Š30%). Amiloride increased significantly total and fractional Na excretion in both groups. Total natriuresis and weight loss were significantly larger in the control group compared with diabetic nephropathy at day 1 of amiloride, whereas fractional Na excretion did not differ. Amiloride intervention increased plasma renin concentration only in diabetic nephropathy group; it reduced SBP in both groups, whereas DBP was reduced in diabetic nephropathy group only. Albuminuria was reduced significantly by amiloride in diabetic nephropathy group. Urine total amiloride concentration was not different between groups (12 ±â€Š1 and 16 ±â€Š1 µmol/l, respectively). Urine total plasminogen and active plasmin were reduced after amiloride in diabetic nephropathy. CONCLUSION: Amiloride increased renal Na excretion, reduced blood pressure, albuminuria, and total and active plasmin in urine. It is concluded that epithelial sodium channel is an attractive target to attain blood pressure control in long-term type I diabetes with no enhanced activity associated with nephropathy.

Hydrator Therapies for Chronic Bronchitis. Lessons from Cystic Fibrosis.

Patients with the chronic bronchitis form of chronic obstructive pulmonary disease and cystic fibrosis share similar clinical features, including mucus obstruction of airways and the development of chronic/recurrent airways infections that often manifest as disease exacerbations. There is growing evidence that these diseases may have parallels in disease pathogenesis as well, including cystic fibrosis transmembrane conductance regulator dysfunction, mucus dehydration, and defective mucociliary clearance. As progress is made in the development of therapies that target the basic defects that lead to cystic fibrosis lung disease, it is possible that similar approaches could also benefit patients with chronic bronchitis. A deeper understanding of how tobacco smoke and other triggers of chronic bronchitis actually lead to disease, and exploration of the concept that therapies that restore cystic fibrosis transmembrane conductance regulator function, mucus hydration, and/or mucociliary clearance may benefit patients with chronic bronchitis, hold the prospect of significant progress in treating this prevalent disease.