Mutations in the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and high serum K ؉ levels (hyperkalemia). WNK4 has distinct functional states that regulate the balance between renal salt reabsorption and K ؉ secretion by modulating the activities of renal transporters and channels, including the Na-Cl cotransporter NCC and the K ؉ channel ROMK. WNK4's functions could enable differential responses to intravascular volume depletion (hypovolemia) and hyperkalemia. Because hypovolemia is uniquely associated with high angiotensin II (AngII) levels, AngII signaling might modulate WNK4 activity. We show that AngII signaling in Xenopus oocytes increases NCC activity by abrogating WNK4's inhibition of NCC but does not alter WNK4's inhibition of ROMK. This effect requires AngII, its receptor AT1R, and WNK4, and is prevented by the AT1R inhibitor losartan. NCC activity is also increased by WNK4 harboring mutations found in PHAII, and this activity cannot be further augmented by AngII signaling, consistent with PHAII mutations providing constitutive activation of the signaling pathway between AT1R and NCC. AngII's effect on NCC is also dependent on the kinase SPAK because dominant-negative SPAK or elimination of the SPAK binding motif in NCC prevent activation of NCC by AngII signaling. These effects extend to mammalian cells. AngII increases phosphorylation of specific sites on SPAK and NCC that are necessary for activation of each in mpkDCT cells. These findings place WNK4 in the signaling pathway between AngII and NCC, and provide a mechanism by which hypovolemia maximizes renal salt reabsoprtion without concomitantly increasing K ؉ secretion.angiotensin II receptor ͉ hypertension ͉ distal convoluted tubule ͉ salt reabsorption ͉ thiazide A ldosterone is released from the adrenal glomerulosa in 2 different physiologic conditions: intravascular volume depletion and hyperkalemia. In the former, aldosterone promotes maximal renal Na-Cl reabsorption to preserve and restore intravascular volume, whereas in the latter renal K ϩ secretion is maximized. Classical explanations for these alternative responses have focused on acute changes in solute delivery to the distal nephron. For example, in volume depletion there is enhanced proximal reabsorption of Na ϩ , which reduces the distal electrogenic reabsorption of Na ϩ via the epithelial sodium channel (ENaC) that is required to establish the electrical gradient necessary for K ϩ secretion.The rare autosomal dominant disease pseudohypoaldosteronism type II (PHAII) suggests there must be additional components that regulate the balance between renal salt reabsorption and potassium secretion. Patients with PHAII have chloridedependent hypertension and hyperkalemia despite otherwise normal renal function and normal aldosterone secretion, suggesting that they constitutively reabsorb Na-Cl at the expense of impaired K ϩ secretion. Missense mutations in the serinethreonine kinase WNK4 have been shown to cause PHAII (1). Subsequent studies in X...

MNP vectors can safely and effectively transfect rodent astrocytes and could form the basis of a 'multifunctional nanoplatform' for neural cell transplantation.

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Remyelination is the phenomenon by which new myelin sheaths are generated around axons in the adult central nervous system (CNS). This follows the pathological loss of myelin in diseases like multiple sclerosis (MS). Remyelination can restore conduction properties to axons (thereby restoring neurological function) and is increasingly believed to exert a neuroprotective role on axons. Remyelination occurs in many MS lesions but becomes increasingly incomplete/inadequate and eventually fails in the majority of lesions and patients. Efforts to understand the causes for this failure of regeneration have fueled research into the biology of remyelination and the complex, interdependent cellular and molecular factors that regulate this process. Examination of the mechanisms of repair of experimental lesions has demonstrated that remyelination occurs in two major phases. The first consists of colonization of lesions by oligodendrocyte progenitor cells (OPCs), the second the differentiation of OPCs into myelinating oligodendrocytes that contact demyelinated axons to generate functional myelin sheaths. Several intracellular and extracellular molecules have been identified that mediate these two phases of repair. Theoretically, the repair of demyelinating lesions can be promoted by enhancing the intrinsic repair process (by providing one or more remyelination-enhancing factors or via immunoglobulin therapy). Alternatively, endogenous repair can be bypassed by introducing myelinogenic cells into demyelinated areas; several cellular candidates have been identified that can mediate repair of experimental demyelinating lesions. Future challenges confronting therapeutic strategies to enhance remyelination will involve the translation of findings from basic science to clinical demyelinating disease.