Abstract: TH-PO1085

Tubular Crosstalk in Renal Calcium Handling

Session Information

Category: Mineral Disease

  • 1204 Mineral Disease: Nephrolithiasis

Authors

  • Bonny, Olivier, University of Lausanne, Lausanne, Switzerland
  • Durussel, Fanny, University of Lausanne, Lausanne, Switzerland
  • Ramakrishnan, Suresh Krishna, University of Lausanne, Lausanne, Switzerland
Background

Calciuria is one of the main risk factors for kidney stone and the understanding of its regulation is essential for stone prevention. In the kidney, calcium tubular reabsorption is complex, starting in the proximal tubule (PT) with paracellular reabsorption, continuing in the ascending limb (TAL) with transepithelial paracellular transport through the claudin system and regulation by the basolateral calcium sensing receptor and ending by transcellular calcium reabsorption in the distal convoluted tubule (DCT). When calcium reabsorption is challenged in one specific part of the nephron, reaction in other segments of the nephron has been observed, but not studied systematically. We hypothesized that challenge in one segment is affecting calcium reabsorption in other segments through tubular crosstalk.

Methods

We used mice and challenged renal calcium reabsorption by furosemide (acutely at 4 hours and chronically at 7 days) and thiazide injections or by feeding them with cinacalcet. We microdissected tubular segments and studied the most relevant genes and proteins involved in calcium transport in each segment.

Results

We found that upon acute challenge with furosemide, Nhe3 was downregulated in the proximal tubule, while Cldn16 and 19 were upregulated in the TAL and Trpv5, Ncx1, Pmca4 and calbindin 28 and 9 were upregulated in the DCT. On chronic furosemide treatment, we observed a shift toward increased proximal and TAL calcium reabsorption, with higher levels of Nhe3, Nkcc2 and CaSR in addition to high levels of Cldn 16 and 19. Interestingly, chronic cinacalcet treatment was increasing NHE3 and CaSR expression. In the DCT, NCC was upregulated, but Trpv5 and other more distal genes involved in calcium transport were not changed. Thiazide challenge did not modify expression of the tested genes acutely (4 hours), but chronically was increasing NHE3 (protein level) and some distal genes.

Conclusion

Altogether, this data show that tubular crosstalk is part of the intrarenal regulation of calciuria. The precise mechanisms leading to tubular adaptation to a segment-specific calcium reabsorption challenge still need further studies.

Funding

  • Government Support - Non-U.S.