Kidney Loop of Henle GO Cocuration Project

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Kidney Loop of Henle GO Cocuration

Yasmin Alam-Faruque and Emily Dimmer.

  • As the renal community is embracing proteomic technologies at an increasing rate to identify, quantify and characterize a global set of proteins then there is a need to provide a high quality information-rich functional dataset that can be utilized by them to rapidly evaluate new data and generate hypotheses to guide future research seeking to alleviate renal diseases (1,11).
  • Nephrons are the functional units of the kidney. Each nephron consists of 2 parts: a renal corpuscle where blood plasma is filtered and a renal tubule into which the filtered blood passes. The two components of a renal corpuscle are the glomerulus (capillary network) and the glomerular (Bowman’s) capsule (a double-walled epithelial cup surrounding the glomerular capillaries. Blood plasma is first filtered in the glomerular capsule and then passes into the renal tubule, comprised of 3 main sections: (i) the proximal convoluted tubule, (ii) the loop of Henle (nephron loop) and (iii) distal convoluted tubule. The renal corpuscle and both convoluted tubules lie within the renal cortex whereas the loop of Henle extends into the renal medulla, makes a hairpin turn and then returns to the renal cortex.
  • The main function of the loop of Henle is to create a concentration gradient in the medulla of the kidney and investigators are looking into how the renal concentrating mechanism works in-vivo (2). By means of a mechanism which utilizes sodium pumps, it creates an area of high sodium concentration deep in the medulla, near the collecting duct. Water present in the filtrate in the collecting duct flows through aquaporin channels out of the collecting duct, moving passively down its concentration gradient. This process reabsorbs water and creates a concentrated urine for excretion. The loop of Henle is also involved in reabsorption of filtered Na+, K+, Ca2+, HCO3- Cl- and H2O, and is hence involved in independent regulation of both volume and osmolarity of body fluids. There are various mechanisms in place for this function e.g. For Na+ and Cl-, reabsorption occurs by means of Na+Cl- symporters in the apical membranes; Na+-K+ pumps and Cl- leakage channels in the basolateral menbranes, and the distal convoluted tubule is the major site of parathyroid hormone stimulating reabsorption of Ca2+. There are many genes important for the development and function of the mammalian kidney e.g.: COX-2 has a significant role in the fetal human kidney involved in the development of the nephron (3), and the NADPH oxidases which have a distinct cellular localization in renal vessels including cells of the thick ascending limb of the loop of Henle, may have an important pathophysiological role in regulating angiotensin and salt concentrations (4).
  • The pronephros, mesonephros and metanephros represent three distinct renal organs that function in succession as the vertebrate excretory system during development of the kidney. These three organ systems are derived from intermediate mesoderm and develop according to an ordered temporal process.
  • The loop of Henle structure of the kidney differs considerably between mammals, chicken and frogs. There is a definite loop of Henle structure in the mammalian and avian systems but this physical structure seems to be absent in the frog. However the segment(s) for the area in which the loop of Henle develops is present in Xenopus (Duncan Davidson and Jamie Davies GUDMAP, Personal communication).
  • The renal community consider the Xenopus pronephros as an ideal model for investigating organogenesis and development of renal function in vertebrates (5,6) since Xenopus has been studied and analyzed for many decades and is already a simple and popular animal model for developmental cell biologists.
  • In the avian kidney, 3 types of nephron are identified: mammalian-type nephrons with long and short loops of Henle, and reptilian type nephrons (7).
  • The renal community has also used the chicken in their studies investigating amino acid transport process across cell membranes (8).
Work Plan
  • From speaking with renal researchers at GUDMAP, the loop of Henle structure was thought to be an interesting subject – as the structure is known to change rapidly between different organisms (see above). Therefore it would be interesting to see how functions of gene products in mammalian, avian and amphibian species change during the evolution of the loop of Henle structure.
  • We thought that perhaps a concurrent GO annotation exercise by curators on orthologous genes in the human/mouse, chicken and Xenopus species might result in quite a nice publication. The loop of Henle might be an ideal focus as there would be enough genes to create a large-enough annotation set to be able to analyse well, yet not too many for us to be overwhelmed by the amount of effort required for such a project!
  • Individual studies on the functional specialization of orthologous genes in distinct species has been carried out for single genes (e.g. the Na-K-Cl cotransporter); (9), and also papers describing the comparative anatomy of different loop of Henle structures (10), however this project will enable a wide review of the functional information available for orthologs of genes in different species.
  • Such a target list could be obtained from looking at GUDMAP gene expression database, which provides those genes shown to be specifically expressed in the murine loop of Henle; .
  • From a list of 155 mouse genes expressed in the loop of Henle, 126 Ensembl identifiers for orthologues in Xenopus tropicalis, 65 UniProtKB accessions obtained for chicken (Gallus gallus), 83 UniProtKB accessions for human and 84 UniProtKB accessions for rat have been located from initial searches using Clustr and Ensembl BioMart. It is likely additional orthologs will be located during the project for these organisms, and additional genes known to be important in the Loop of Henle would supplement this list during the project.
  • A quick review of the first 15 in this list, using the NCBI PubMed resource, found that 13 of the 15 appear to have some known kidney-related function (indicating that the method used to generate the list appears viable), that human/mouse have publications for all of selected genes, whereas the chicken ortholog have publications for 13, and Xenopus for 11 of the selected 15 genes; indicating that there appears to be enough literature to support this curation effort in each of the three species.
  • Curators will be asked to annotate a maximum of 200 proteins, with those genes that over-lap with those targeted by the AgBase team prioritized.
  • It is envisaged that this project will take around 8-12 months to complete since it will not be worked on full-time by the Xenopus and chicken curators, and will need to fit in with the priorities of these different groups. Progress will be monitored and reported to the groups involved at quarterly intervals. A central document page will be developed by Yasmin (probably using a GO wiki) which will be accessible by all concerned. This page will act as a central resource for the project and list all the genes names and corresponding accessions for each organism that will be targeted by this project. This will help in monitoring the progress of this project, highlight interesting points/difficulties, supported by email communication between all the curators involved.
  • The annotations will be analyzed at the end of the project, to highlight the most frequent reasons for the functional differences between species – such as lack/addition of specific splice variants, with unique functional characteristics between the species. Changes will also be displayed visually n GO slim views compare each of the proteomes.
  • Contacts with kidney experts will be made for each of the three species, to seek additional value for the project.
  • The benefits in this project include:
    • focused development of GO terms to more accurately describe renal-associated processes
    • instigate contacts with renal groups who might be interested in contributing to this project
    • UniProtKB will receive feedback where information is available for improvement of Swiss-Prot entries.
    • generation of a publication which will:
      • highlight not only biological insights into the similarities and differences of the orthologous genes in these distinct species
      • demonstrate the usefulness of focused, collaborative cross-species GO annotation
      • demonstrate to users the usefulness of functional annotation associated with specific UniProtKB accessions
      • provide publicity for the UniProtKB, AgBase and GOA resources.
      • publicity for the Renal annotation initiative; encourage feedback and possible future collaborations.

1. Janech MG, Raymond JR, Arthur JM (2007); Proteomics in renal research; Am J Pysiol Renal Physiol; 292(2), F501-12 (PMID 17107941).

2. Halperin ML, Kamel KS, Oh MS (2008); Mechanisms to concentrate the urine: an opinion. Curr Opin Nephrol Hypertens; 17(4), 416-22 (PMID 18660679).

3. Khan KN, Stanfield KM et al; (2001); Cylooxygenase-2-expression in the developing human kidney Pediatr Dev Path 4(4) 461-6 (PMID 11779048).

4. Chan T, Asashima M (2006) Growing kidney in the Frog; Nephron Exp Nephrol; 103, e81-85 (PMID 16554664).

5. Gill PS, Wilcox CS (2006); NADPH oxidases in the kidney; Antioxid Redox Signal 8(9-10), 1597-607 (PMID 16987014).

6. Jones EA (2005); Xenopus: a prince among models for pronephric kidney development; J Am Soc Nephrol 16(2), 313-21 (PMID 15647339).

7. Gambaryan SP (1992); Development of the metanephros in the chick: maturation of glomerular size and nephron length; Anat Embryol (Berl); 185(3):291-7. (PMID 1575329).

8. Lerner J (1984) Cell membrane amino acid transport processes in the domestic fowl (Gallus domesticus). Comp Biochem Physiol A Comp Physiol; 78(2):205-15. (PMID 6146442).

9. Gagnon E, Forbush B, Caron L, Isenring P.(2003) Functional comparison of renal Na-K-Cl cotransporters between distant species. Am J Physiol Cell Physiol.284(2):C365-70. (PMID 12388059).

10. Bankir L, and de Rouffignac C. (1985) Urinary concentrating ability : insights from comparative anatomy. Am. J. Physiol. Regulatory Integrative Comp. Physiol. 249: p.643-666. (PMID 3934988)

11. Dihazi H, Rahman AA, Agarwal NK, Doncheva Y, Muller GA (2005) Proteomics analysis of cellular response to osmotic stress in TALH-cells. Mol. Cell Proteomics 4: 1445-1458.(PMID 15975915)

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