Epithelial Systems Biology Laboratory

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Systems Biology of the Collecting Duct

Vasopressin regulates the osmotic water permeability of the collecting duct epithelium through actions in at least two time frames (7): 1) short-term effects to stimulate membrane trafficking events that redistribute aquaporin-2 from inside the cell to the apical plasma membrane (time frame, 5-40 minutes); 2) long-term effects to increase the total amount of cellular aquaporin-2 and aquaporin-3 (time frame, 16-48 hours). These effects are mediated by binding of vasopressin to the V2 receptor in the basolateral plasma membrane. The chief goal of the Epithelial Systems Biology Laboratory (ESBL) is to identify the cellular mechanisms that provide a connection between changes in the extracellular concentration of vasopressin and the two modes of aquaporin-2 regulation.

The identification of the causal connection between the input and output can be pursued in two ways, both utilized in the ESBL. First, a reductionist approach examines the role of one protein at a time. Second, a systems biology-based approach seeks to study all relevant components of the system in parallel (4). To a large extent, the relevant components are the various protein species expressed in the cell. Consequently, the ESBL has exploited proteomics approaches, which use the power of modern mass spectrometry to identify and quantify thousands of proteins in individual experiments (5, 6). More recently, the introduction of deep sequencing methodologies (3) allows large-scale identification and quantification of transcripts (RNA-seq) and points of protein binding along the genome (ChIP-seq) (1, 2). Ultimately, the challenge is to integrate data sets derived from these large-scale systems level studies with other types of data to develop models of physiological function.

References:

  1. Jung HJ, Raghuram V, Lee JW, Knepper MA. Genome-Wide Mapping of DNA Accessibility and binding sites for CREB and C/EBPβ in vasopressin-sensitive collecting duct cells. J Am Soc Nephrol. 2018; 29:1490-1500. PMID: 29572403.

  2. Sandoval PC, Claxton JS, Lee JW, Saeed F, Hoffert JD, Knepper MA. Systems-level analysis reveals selective regulation of Aqp2 gene expression by vasopressin. Sci Rep. 2016; 6:34863. PMID: 27725713.

  3. Lee JW, Chou CL, Knepper MA. Deep sequencing in microdissected renal tubules identifies nephron segment-specific transcriptomes. J Am Soc Nephrol. 2015 Mar 27. PubMed PMID: 25817355.

  4. Knepper MA. Systems biology in physiology: the vasopressin signaling network in kidney. Am J Physiol Cell Physiol. 2012; 303: C1115-24. PMID: 22932685.

  5. Hoffert JD, Chou CL, Knepper MA. Aquaporin-2 in the "-omics" era. J Biol Chem. 2009; 284: 14683-7. PMID: 19193633.

  6. Pisitkun T, Hoffert JD, Yu MJ, Knepper MA. Tandem mass spectrometry in physiology. Physiology (Bethesda). 2007; 22:390-400. PMID: 18073412.

  7. Nielsen S, Frokiaer J, Marples D, Kwon TH, Agre P, Knepper MA. Aquaporins in the kidney: from molecules to medicine. Physiol Rev. 2002; 82: 205-44. PMID: 11773613.