Potassium homeostasis and dyskalemias: the respective roles of renal, extrarenal, and gut sensors in potassium handling.

Integrated mechanisms controlling the maintenance of potassium homeostasis are well established and are defined by the classic "feedback control" of potassium balance. Recently, increasing investigative attention has focused on novel physiological paradigms that increase the complexity and precision of homeostasis. This review briefly considers the classic and well-established feedback control of potassium and then considers subsequent investigations that inform on an intriguing and not widely recognized complementary paradigm: the "feed-forward control of potassium balance." Feed-forward control refers to a pathway in a homeostatic system that responds to a signal in the environment in a predetermined manner, without responding to how the system subsequently reacts (i.e., without responding to feedback). Studies in several animal species, and recently in humans, have confirmed the presence of a feed-forward control mechanism that is capable of mediating potassium excretion independent of changes in serum potassium concentration and aldosterone. Knowledge imparted by this update of potassium homeostasis hopefully will facilitate the clinical management of hyperkalemia in patients with chronic and recurrent hyperkalemia. Awareness of this updated integrative control mechanism for potassium homeostasis is more relevant today when the medical community is increasingly focused on leveraging and expanding established renin-angiotensin-aldosterone system inhibitor treatment regimens and on successfully coping with the challenges of managing hyperkalemia provoked by renin-angiotensin-aldosterone system inhibitors. These new insights are relevant to the future design of clinical trials delineating renal potassium handling.

The Unappreciated Role of Extrarenal and Gut Sensors in Modulating Renal Potassium Handling: Implications for Diagnosis of Dyskalemias and Interpreting Clinical Trials.

In addition to the classic and well-established "feedback control" of potassium balance, increasing investigative attention has focused on a novel and not widely recognized complementary regulatory paradigm for maintaining potassium homeostasis-the "feed-forward control" of potassium balance. This regulatory mechanism, initially defined in rumen, has recently been validated in normal human subjects. Studies are being conducted to determine the location for this putative potassium sensor and to evaluate potential signals, which might increase renal potassium excretion. Awareness of this more updated integrative control mechanism for potassium homeostasis is ever more relevant today, when the medical community is increasingly focused on the challenges of managing the hyperkalemia provoked by renin-angiotensin-aldosterone system inhibitors (RAASis). Recent studies have demonstrated a wide gap between RAASi prescribing guidelines and real-world experience and have highlighted that this gap is thought to be attributable in great part to hyperkalemia. Consequently we require a greater knowledge of the complexities of the regulatory mechanisms subserving potassium homeostasis. Sodium polystyrene sulfonate has long been the mainstay for treating hyperkalemia, but its administration is fraught with challenges related to patient discomfort and colonic necrosis. The current and imminent availability of newer potassium binders with better tolerability and more predictive dose-response potassium removal should enhance the management of hyperkalemia. Consequently it is essential to better understand the intricacies of mammalian colonic K+ handling. We discuss colonic transport of K+ and review evidence for potassium (BK) channels being responsible for increased stool K+ in patients with diseases such as ulcerative colitis.

Aldosterone blockade and the mineralocorticoid receptor in the management of chronic kidney disease: current concepts and emerging treatment paradigms.

The past two decades have witnessed a striking paradigm shift with respect to our understanding of the widespread effects of aldosterone. There is substantive evidence that mineralocorticoid receptor (MR) activation promotes myriad 'off target' effects on the heart, the vasculature, and importantly the kidney. In the present review, we summarize the expanding role of MR activation in promoting both vascular and renal injury. We review the recent clinical studies that investigated the efficacy of MR antagonism (MRA) in reducing proteinuria and attenuating progressive renal disease. We also review in-depth both the utility and safety of MRA in the end-stage renal disease (ESRD) patient undergoing dialysis. Because the feasibility of add-on MRA is critically dependent on our ability to minimize or avoid hyperkalemia, and because controversy centers on the incidence of hyperkalemia, we critically review the risk of hyperkalemia with add-on MRA. Our present analysis suggests that hyperkalemia supervening in MRA-treated patients is overstated. Furthermore, recent studies demonstrating the efficacy of new non-absorbed, orally administered, potassium [K+]-binding polymers suggest that a multi-pronged approach encompassing adequate surveillance, moderate or low-dose MRA, and K-binding polymers may adequately control serum K in both chronic kidney disease and ESRD patients.

Epidermal growth factor upregulates beta-adrenergic receptor signaling in a human salivary cell line.

The effects of epidermal growth factor (EGF) on the beta-adrenergic receptor-coupled adenylyl cyclase system were studied in a human salivary cell line (HSY). The beta-adrenergic agonist isoproterenol (10(-5) M) stimulated adenylyl cyclase activity by approximately 2-fold, and the isoproterenol response was increased 1.8-fold after prolonged (48 h) exposure to EGF (5 x 10(-10) M). In contrast, enzyme activation via stimulatory prostaglandin receptors and by agents acting on nonreceptor components of the adenylyl cyclase system was not enhanced by EGF. beta-Adrenergic receptor density, assessed by binding of the beta-adrenergic receptor antagonist (-)-[(125)I]iodopindolol, was increased threefold after EGF treatment. Competition binding studies with unlabeled antagonists selective for beta(1)- and beta(2)-adrenergic receptor subtypes indicated that the increase in (-)-[(125)I]iodopindolol binding sites induced by EGF reflected an increased number of beta(2)-adrenergic receptors. Likewise, Northern blot analysis of RNA from EGF-treated cells revealed selective induction of beta(2)-adrenergic receptor mRNA, which was blocked by the RNA synthesis inhibitor actinomycin D. The increase in beta-adrenergic receptor density produced by EGF was unaltered after phorbol ester-induced downregulation of protein kinase C (PKC). Enhancement of isoproterenol-responsive adenylyl cyclase activity and phosphorylation of mitogen-activated protein kinase (MAPK) by EGF were both blocked by the MAPK pathway inhibitor PD-98059. The results suggest that in HSY cells EGF enhances beta-adrenergic responsiveness by upregulating beta(2)-adrenergic receptor expression at the transcriptional level. Moreover, the stimulatory effect of EGF on beta(2)-adrenergic receptor signaling appears to be mediated by the MAPK pathway and independent of PKC activation.

Epidermal growth factor-induced depletion of the intracellular Ca2+ store fails to activate capacitative Ca2+ entry in a human salivary cell line.

Epidermal growth factor (EGF) is a multifunctional factor known to influence proliferation and function of a variety of cells. The actions of EGF are mediated by EGF receptor tyrosine kinase pathways, including stimulation of phospholipase Cgamma and mobilization of intracellular Ca(2+) ([Ca(2+)](i)). Generally, agonist-mediated Ca(2+) mobilization involves both Ca(2+) release from internal stores and Ca(2+) influx activated by store depletion (i.e. capacitative or store-operated Ca(2+) influx). However, the role of capacitative Ca(2+) entry in EGF-mediated Ca(2+) mobilization is still largely unknown. In this study, we compared [Ca(2+)](i) signals elicited by EGF with those induced by agents (the muscarinic receptor agonist carbachol and thapsigargin (Tg)) known to activate capacitative Ca(2+) entry. Unlike carbachol and Tg, EGF (5 nm) elicited a transient [Ca(2+)](i) signal without a plateau phase in the presence of extracellular Ca(2+) and also failed to accelerate Mn(2+) entry. Repletion of extracellular Ca(2+) to cells stimulated with EGF in the absence of Ca(2+) elicited an increase in [Ca(2+)](i), indicating that EGF indeed stimulates Ca(2+) influx. However, the influx was activated at lower EGF concentrations than those required to stimulate Ca(2+) release. Interestingly, the phospholipase C inhibitor completely inhibited Ca(2+) release induced by both EGF and carbachol and also reduced Ca(2+) influx responsive to carbachol but had no effect on Ca(2+) influx induced by EGF. EGF-induced Ca(2+) influx was potentiated by low concentrations (<5 ng/ml) of oligomycin, a mitochondrial inhibitor that blocks capacitative Ca(2+) influx in other systems. Transient expression of the hTRPC3 protein enhanced Ca(2+) influx responsive to carbachol but did not increase EGF-activated Ca(2+) influx. Both EGF and carbachol depleted internal Ca(2+) stores. Our results demonstrate that EGF-induced Ca(2+) release from internal stores does not activate capacitative Ca(2+) influx. Rather, EGF stimulates Ca(2+) influx via a mechanism distinct from capacitative Ca(2+) influx induced by carbachol and Tg.