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Hypercalciuria switches Ca(2+) signaling in proximal tubular cells, induces oxidative damage to promote calcium nephrolithiasis
Proximal tubule (PT) transports most of the renal Ca(2+), which was usually described as paracellular (passive). We found a regulated Ca(2+) entry pathway in PT cells via the apical transient receptor potential canonical 3 (TRPC3) channel, which initiates transcellular Ca(2+) transport. Although TRP...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Chongqing Medical University
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8843860/ https://www.ncbi.nlm.nih.gov/pubmed/35224165 http://dx.doi.org/10.1016/j.gendis.2021.04.006 |
Sumario: | Proximal tubule (PT) transports most of the renal Ca(2+), which was usually described as paracellular (passive). We found a regulated Ca(2+) entry pathway in PT cells via the apical transient receptor potential canonical 3 (TRPC3) channel, which initiates transcellular Ca(2+) transport. Although TRPC3 knockout (−/−) mice were mildly hypercalciuric and displayed luminal calcium phosphate (CaP) crystals at Loop of Henle (LOH), no CaP + calcium oxalate (CaOx) mixed urine crystals were spotted, which are mostly found in calcium nephrolithiasis (CaNL). Thus, we used oral calcium gluconate (CaG; 2%) to raise the PT luminal [Ca(2+)](o) further in TRPC3(−/−) mice for developing such mixed stones to understand the mechanistic role of PT-Ca(2+) signaling in CaNL. Expectedly, CaG-treated mice urine samples presented with numerous mixed crystals with remains of PT cells, which were pronounced in TRPC3(−/−) mice, indicating PT cell damage. Notably, PT cells from CaG-treated groups switched their mode of Ca(2+) entry from receptor-operated to store-operated pathway with a sustained rise in intracellular [Ca(2+)] ([Ca(2+)](i)), indicating the stagnation in PT Ca(2+) transport. Moreover, those PT cells from CaG-treated groups demonstrated an upregulation of calcification, inflammation, fibrotic, oxidative stress, and apoptotic genes; effects of which were more robust in TRPC3 ablated condition. Furthermore, kidneys from CaG-treated groups exhibited fibrosis, tubular injury and calcifications with significant reactive oxygen species generation in the urine, thus, indicating in vivo CaNL. Taken together, excess PT luminal Ca(2+) due to escalation of hypercalciuria in TRPC3 ablated mice induced surplus CaP crystal formation and caused stagnation of PT [Ca(2+)](i), invoking PT cell injury, hence mixed stone formation. |
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