Overview of Aerosolized Florida Red Tide Toxins: Exposures and Effects

Florida red tide is caused by Karenia brevis, a dinoflagellate that periodically blooms, releasing its potent neurotoxin, brevetoxin, into the surrounding waters and air along the coast of the Gulf of Mexico. Exposure to Florida red tide toxins has been associated with adverse human health effects and massive fish and marine mammal deaths. The articles in this mini-monograph describe the ongoing interdisciplinary and interagency research program that characterizes the exposures and health effects of aerosolized Florida red tide toxins (brevetoxins). The interdisciplinary research program uses animal models and laboratory studies to develop hypotheses and apply these findings to in situ human exposures. Our ultimate goal is to develop appropriate prevention measures and medical interventions to mitigate or prevent adverse health effects from exposure to complex mixtures of aerosolized red tide toxins

Proliferation of Acid-Secretory Cells in the Kidney during Adaptive Remodelling of the Collecting Duct

The renal collecting duct adapts to changes in acid-base metabolism by remodelling and altering the relative number of acid or alkali secreting cells, a phenomenon termed plasticity. Acid secretory A intercalated cells (A-IC) express apical H+-ATPases and basolateral bicarbonate exchanger AE1 whereas bicarbonate secretory B intercalated cells (B-IC) express basolateral (and apical) H+-ATPases and the apical bicarbonate exchanger pendrin. Intercalated cells were thought to be terminally differentiated and unable to proliferate. However, a recent report in mouse kidney suggested that intercalated cells may proliferate and that this process is in part dependent on GDF-15. Here we extend these observations to rat kidney and provide a detailed analysis of regional differences and demonstrate that differentiated A-IC proliferate massively during adaptation to systemic acidosis. We used markers of proliferation (PCNA, Ki67, BrdU incorporation) and cell-specific markers for A-IC (AE1) and B-IC (pendrin). Induction of remodelling in rats with metabolic acidosis (with NH4Cl for 12 hrs, 4 and 7 days) or treatment with acetazolamide for 10 days resulted in a larger fraction of AE1 positive cells in the cortical collecting duct. A large number of AE1 expressing A-IC was labelled with proliferative markers in the cortical and outer medullary collecting duct whereas no labeling was found in B-IC. In addition, chronic acidosis also increased the rate of proliferation of principal collecting duct cells. The fact that both NH4Cl as well as acetazolamide stimulated proliferation suggests that systemic but not urinary pH triggers this response. Thus, during chronic acidosis proliferation of AE1 containing acid-secretory cells occurs and may contribute to the remodelling of the collecting duct or replace A-IC due to a shortened life span under these conditions

The anion exchanger pendrin (SLC26A4) and renal acid-base homeostasis

The anion exchanger pendrin (Pds, SLC26A4) transports various anions including bicarbonate, chloride and iodide. In the kidney, pendrin is exclusively expressed on the luminal pole of bicarbonate-secretory type B intercalated cells. Genetic ablation of pendrin in mice abolishes luminal chloride-bicarbonate exchanger activity from type B intercalated cells suggesting that pendrin is the apical bicarbonate extruding pathway. The renal expression of pendrin is developmentally adapted and pendrin positive cells originate from both the uretric bud and mesenchyme. In adult kidney, pendrin expression and activity is regulated by systemic acid-base status, dietary electrolyte intake (mostly chloride), and hormones such as angiotensin II and aldosterone which can affect subcellular localization, the relative number of pendrin expressing cells, and the overall abundance consistent with a role of pendrin in maintaining normal acid-base homeostasis. This review summarizes recent findings on the role and regulation of pendrin in the context of the kidneys role in acid-base homeostasis in health and disease

Regulated acid-base transport in the collecting duct

The renal collecting system serves the fine-tuning of renal acid-base secretion. Acid-secretory type-A intercalated cells secrete protons via a luminally expressed V-type H(+)-ATPase and generate new bicarbonate released by basolateral chloride/bicarbonate exchangers including the AE1 anion exchanger. Efficient proton secretion depends both on the presence of titratable acids (mainly phosphate) and the concomitant secretion of ammonia being titrated to ammonium. Collecting duct ammonium excretion requires the Rhesus protein RhCG as indicated by recent KO studies. Urinary acid secretion by type-A intercalated cells is strongly regulated by various factors among them acid-base status, angiotensin II and aldosterone, and the Calcium-sensing receptor. Moreover, urinary acidification by H(+)-ATPases is modulated indirectly by the activity of the epithelial sodium channel ENaC. Bicarbonate secretion is achieved by non-type-A intercalated cells characterized by the luminal expression of the chloride/bicarbonate exchanger pendrin. Pendrin activity is driven by H(+)-ATPases and may serve both bicarbonate excretion and chloride reabsorption. The activity and expression of pendrin is regulated by different factors including acid-base status, chloride delivery, and angiotensin II and may play a role in NaCl retention and blood pressure regulation. Finally, the relative abundance of type-A and non-type-A intercalated cells may be tightly regulated. Dysregulation of intercalated cell function or abundance causes various syndromes of distal renal tubular acidosis underlining the importance of these processes for acid-base homeostasis

Brevetoxins: Toxicological Profile

Brevetoxins (PbTxs) are polyether ladder-shaped neurotoxins produced by the dinoflagellate Karenia brevis. Blooms of K. brevis have been recorded since the mid-1800s, principally in the Gulf of Mexico but occasionally along the mid and south Atlantic coasts. Blooms may be accompanied by public health issues as well as significant mortalities of marine mammals, such as bottlenose dolphins and manatees, fishes, sea birds, and sea turtles. PbTxs bind to the voltage-gated sodium channels (VGSCs), leading to persistent activation of neuronal, muscle, and cardiac cells. In humans, after consumption of contaminated shellfish (oysters, clams, whelks), these toxins cause a syndrome known as neurotoxic shellfish poisoning (NSP), characterized by nausea, diarrhea, vomiting, abdominal pain, paresthesia, myalgia, ataxia, bradycardia, loss of coordination, vertigo, and mydriasis. The ingestion of contaminated seafood represents the most dangerous route of exposure for humans. However, when PbTxs are aerosolized through the disruption of K. brevis cells by breaking waves or winds, people can suffer from respiratory effects such as conjunctivitis, rhinorrhea, and bronchoconstriction. Due to successful shellfish monitoring programs managed by the Gulf coast states, cases of human intoxications are fortunately rather rare, and no human fatalities have been attributed to NSP

Regulation of two renal chloride transporters, AE1 and pendrin, by electrolytes and aldosterone

The renal handling of salt and protons and bicarbonate are intricately linked through shared transport mechanisms for sodium, chloride, protons, and bicarbonate. In the collecting duct, the regulated fine-tuning of salt and acid-base homeostasis is achieved by a series of transport proteins located in different cell types, intercalated and principal cells. Intercalated cells are considered to be of less importance for salt handling but recent evidence has suggested that the anion exchanger pendrin may participate in salt reabsorption and blood pressure regulation. Here, we examined the regulated expression of two functionally related but differentially expressed anion exchangers, AE1 and pendrin, by dietary electrolyte intake and aldosterone. Cortical expression of pendrin was regulated on mRNA and protein level. The combination of NaHCO(3) and DOCA enhanced pendrin mRNA and protein levels, whereas DOCA or NaHCO(3) alone had no effect. NaCl or KHCO(3) increased pendrin mRNA, KCl decreased its mRNA abundance. On protein level, NH(4)Cl, NaCl, and KCl reduced pendrin expression, the other treatments were without effect. In contrast, AE1 mRNA or protein expression in kidney cortex was regulated by none of these treatments. In kidney medulla, NaHCO(3)/DOCA or NaHCO(3) alone enhanced AE1 mRNA levels. AE1 protein abundance was increased by NH(4)Cl, NaHCO(3)/DOCA, and NaCl. Immunolocalization showed that during NH(4)Cl treatment the relative number of AE1 positive cells was increased and pendrin expressing cells reduced. Thus, pendrin and AE1 are differentially regulated with distinct mechanisms that separately affect mRNA and protein levels. Pendrin is regulated by acidosis and chloride intake, whereas AE1 is enhanced by acidosis, NaCl, and the combination of DOCA and NaHCO(3)