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The Rise in Tubular pH during Hypercalciuria Exacerbates Calcium Stone Formation
Farai C Gombedza1, Samuel Shin1,2, Jaclyn Sadiua1
1Calcium Signaling Laboratory, Research Service, Veterans Affairs Medical Center, 50 Irving Street, NW, Washington, DC 20422, USA.
International Journal of Molecular Sciences
|May 11, 2024
Summary
Transient Receptor Potential Canonical type 3 (TRPC3) channel deficiency exacerbates calcium phosphate (CaP) and mixed kidney stone formation in mice under hypercalciuric and alkaline conditions. TRPC3 acts protectively against calcification, fibrosis, inflammation, and apoptosis.
Area of Science:
- Nephrology
- Urology
- Molecular Biology
Background:
- Calcium nephrolithiasis (CaNL) often involves calcium phosphate (CaP) and calcium oxalate (CaOx) crystals.
- Hypercalciuria and elevated urine pH are key factors in CaP crystal nucleation.
- TRPC3 channels regulate proximal tubular calcium (Ca2+) flux, and TRPC3-knockout mice show hypercalciuria and microcrystal formation.
Purpose of the Study:
- To investigate the role of TRPC3 in calcium nephrolithiasis development.
- To determine the impact of TRPC3 deficiency on CaP and mixed crystal formation under hypercalciuric and alkaline conditions.
Main Methods:
- Utilized TRPC3-knockout (KO) mice treated with calcium gluconate (CaG) and acetazolamide (ACZ) to induce a CaNL phenotype.
- Analyzed crystal formation, size, and distribution in kidney tissues.
- Assessed Ca2+ entry in proximal tubular (PT) cells using store-operated Ca2+ entry (SOCE) and receptor-operated Ca2+ entry (ROCE) inhibitors.
- Evaluated gene expression profiles in PT cells.
Main Results:
- TRPC3 KO mice treated with CaG and ACZ (KOT) exhibited significantly greater CaP and mixed crystal formation compared to wild-type controls (WTT).
- KOT mice showed markedly larger crystal sizes and increased microcrystal deposition in kidney medullary and calyceal regions.
- PT cells from treated mice showed altered Ca2+ entry, with TRPC3 deficiency impacting ROCE and SOCE mechanisms.
- Gene expression analysis revealed a protective role for TRPC3 against calcification, fibrosis, inflammation, and apoptosis under high pH and hypercalciuric conditions.
Conclusions:
- TRPC3 deficiency, combined with hypercalciuria and elevated urine pH, significantly promotes CaP and mixed kidney stone formation.
- Compromised ROCE and SOCE mechanisms in TRPC3-deficient cells contribute to increased lithiasis.
- TRPC3 plays a crucial protective role against kidney calcification and associated pathologies in a CaNL model.
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