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Abstract: SA-PO513

Soluble Klotho Anchors TRPV5 on Membrane Independent of FGFR1 by Binding TRPV5 and Galectin 1 Simultaneously

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Lee, Jinho, Seoul National University Hospital, Seoul, Korea (the Republic of)
  • Bodokhsuren, Tsogbadrakh Bodokhsuren, Seoul National University Hospital, Seoul, Korea (the Republic of)
  • Ryu, Hyunjin, Seoul National University Hospital, Seoul, Korea (the Republic of)
  • Kang, Eunjeong, Seoul National University Hospital, Seoul, Korea (the Republic of)
  • Kang, Minjung, Seoul National University Hospital, Seoul, Korea (the Republic of)
  • Ahn, Curie, Seoul National University Hospital, Seoul, Korea (the Republic of)
  • Oh, Kook-Hwan, SNU College of Medicine, Seoul, Korea (the Republic of)
Background

Hypercalciuria is one of the early disturbances of diabetic nephropathy (DN). This is partially due to decrease of renal transient receptor potential vanilloid type 5 (TRPV5) expression, which is responsible for renal calcium reabsorption. Soluble klotho was previously known to increase TRPV5 by cleaving sialic acid, causing TRPV5 to bind to a membrane protein galectin 1. However, recent study showed that soluble klotho binds to a2-3-sialyllactose - where sialic acid is located - on TRPV5, rather than cleave it.

Methods

We injected recombinant soluble klotho protein(rKL) into db/db and db/m mice for 8 weeks, and collected urine and the kidney. We treated rKL, AZD4547 (FGFR1 inhibitor), and OTX008 (Galectin 1 inhibitor) to mouse distal tubular cells, with or without 30mM high glucose (HG) exposed.

Results

db/db mice showed increased renal calcium excretion, and decreased renal TRPV5 expression. rKL treatment reversed this change. In vitro, TRPV5 expression in distal tubular cells decreased in HG situation, and rKL successfully upregulated TRPV5 with or without AZD4547. Also, immunofluorescence for klotho, TRPV5 and glaectin 1 are the same location in distal tubule cells, suggesting that klotho binds to both TRPV5 and galectin 1. However, when AZD4547 and OTX008 are both treated, rKL failed to increase TRPV5 in HG condition.

Conclusion

rKL binds to both TRPV5 and galectin1, thereby tethers TRPV5 on apical membrane. This soluble klotho-mediated holding TRPV5 on apical membrane is FGFR1 independent, but galectin 1 dependent.

in db/db mice, rKL increased renal TRPV5 and decreased urinary calcium excretion. In vitro, rKL failed to increase TRPV5 when both FGFR1 and galectin 1 are inhibited.

Funding

  • Government Support - Non-U.S.