Renal epithelial cell plasma membranes are divided into two domains whose distinct biochemical compositions reflect their individual roles. This polarity is required for vectorial solute and fluid transport in the kidney. To achieve this asymmetry, an epithelial cell must be able to establish distinct surface domains and to maintain these domains'distinct identities. The generation and maintenance of epithelial polarity is dependent upon the formation of contacts between neighboring cells, which initiates signals that activate the assembly of intercellular junctions and their associated polarization machinery. We and others have shown that adenosine monophosphate-stimulated protein kinase (AMPK) plays a key role in the formation of intercellular junctions and in the establishment of polarity. AMPK is a cellular energy sensor activated by intracellular ATP depletion that helps to protect tissues from the consequences of energy deprivation. AMPK governs numerous pathways that modulate cell growth and metabolism. Extracellular calcium plays a critical and complex role in inducing junction assembly, and we find that the calcium sensing receptor (CaSR) contributes to calcium- dependent junction assembly. We have also found that initiation of junction formation leads to inhibition of the GSK3? kinase, which regulates a number of cell differentiation and polarization signaling pathways. We wish to understand the roles that AMPK, GSK3?, the CaSR and other regulatory molecules play in the establishment and preservation of epithelial polarity under normal circumstances and in the face of pathological perturbations such as energy deprivation. We propose to determine 1) how modulation of the activities of AMPK, GSK3? and the CaSR initiate tight junction formation and influence tight junction protein expression;2) how the AMPK, GSK3? and CaSR pathways influence established junctions in intact epithelia;and 3) how loss of AMPK activity affects renal function and the susceptibility of renal tubular epithelial cells to ischemic damage. Through these studies, we will identify new regulatory targets and control points in the complex process of epithelial polarization. We will also invesigate cellular pathways involved in acute kidney injury and possible therapeutic interventions that may mitigate its severity.
Kidney epithelial cells are designed to transport salt and water, with surface membranes that are divided into two domains separated by junctions that connect neighboring cells and that control the flow of substances between them. A number of regulatory processes control the formation of these junctions. Understanding these processes is critical to understanding the normal function of the kidney and its response to injury.
|Han, Jaeyong; Lee, Seung Hun; Giebisch, Gerhard et al. (2016) Potassium Channelopathies and Gastrointestinal Ulceration. Gut Liver 10:881-889|
|Stoops, Emily H; Hull, Michael; Caplan, Michael J (2016) Newly synthesized and recycling pools of the apical protein gp135 do not occupy the same compartments. Traffic 17:1272-1285|
|Ishizawa, Kenichi; Xu, Ning; Loffing, Johannes et al. (2016) Potassium depletion stimulates Na-Cl cotransporter via phosphorylation and inactivation of the ubiquitin ligase Kelch-like 3. Biochem Biophys Res Commun 480:745-751|
|Ferdaus, Mohammed Z; Barber, Karl W; LÃ³pez-Cayuqueo, Karen I et al. (2016) SPAK and OSR1 play essential roles in potassium homeostasis through actions on the distal convoluted tubule. J Physiol 594:4945-66|
|Scholl, Ute I; StÃ¶lting, Gabriel; Nelson-Williams, Carol et al. (2015) Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. Elife 4:e06315|
|Chen, Tiane; Kocinsky, Hetal S; Cha, Boyoung et al. (2015) Cyclic GMP kinase II (cGKII) inhibits NHE3 by altering its trafficking and phosphorylating NHE3 at three required sites: identification of a multifunctional phosphorylation site. J Biol Chem 290:1952-65|
|Oza, Javin P; Aerni, Hans R; Pirman, Natasha L et al. (2015) Robust production of recombinant phosphoproteins using cell-free protein synthesis. Nat Commun 6:8168|
|Lin, Dao-Hong; Yue, Peng; Yarborough 3rd, Orlando et al. (2015) Src-family protein tyrosine kinase phosphorylates WNK4 and modulates its inhibitory effect on KCNJ1 (ROMK). Proc Natl Acad Sci U S A 112:4495-500|
|Pirman, Natasha L; Barber, Karl W; Aerni, Hans R et al. (2015) A flexible codon in genomically recoded Escherichia coli permits programmable protein phosphorylation. Nat Commun 6:8130|
|Farr, Glen A; Hull, Michael; Stoops, Emily H et al. (2015) Dual pulse-chase microscopy reveals early divergence in the biosynthetic trafficking of the Na,K-ATPase and E-cadherin. Mol Biol Cell 26:4401-11|
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