Hypercalciuria switches Ca2+ signaling in proximal tubular cells, induces oxidative damage to promote calcium nephrolithiasis

Samuel Shin; Cliff-Lawrence Ibeh; Eugenia Awuah Boadi; Bok-Eum Choi; Sanjit K. Roy; Bidhan C. Bandyopadhyay

doi:10.1016/j.gendis.2021.04.006

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Hypercalciuria switches Ca2+ signaling in proximal tubular cells, induces oxidative damage to promote calcium nephrolithiasis

Full-length article | 更新时间：2022-06-24

- Hypercalciuria switches Ca2+ signaling in proximal tubular cells, induces oxidative damage to promote calcium nephrolithiasis
- Hypercalciuria switches Ca2+ signaling in proximal tubular cells, induces oxidative damage to promote calcium nephrolithiasis
- Genes & Diseases 2022年9卷第2期
- 作者机构：
  
  Calcium Signaling Laboratory, Research Service, Veterans Affairs Medical Center, 50 Irving Street,,, DC,Washington,NW,USA,20422
- 作者简介：
- 基金信息：
- DOI：10.1016/j.gendis.2021.04.006
  中图分类号：
- 纸质出版日期：2022，
  
  网络出版日期：2022-3-1，
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Samuel Shin, Cliff-Lawrence Ibeh, Eugenia Awuah Boadi, 等. Hypercalciuria switches Ca2+ signaling in proximal tubular cells, induces oxidative damage to promote calcium nephrolithiasis[J]. Genes & Diseases, 2022,9(2).

Samuel Shin, Cliff-Lawrence Ibeh, Eugenia Awuah Boadi, et al. Hypercalciuria switches Ca2+ signaling in proximal tubular cells, induces oxidative damage to promote calcium nephrolithiasis[J]. Genes & Diseases, 2022,9(2).
Samuel Shin, Cliff-Lawrence Ibeh, Eugenia Awuah Boadi, 等. Hypercalciuria switches Ca2+ signaling in proximal tubular cells, induces oxidative damage to promote calcium nephrolithiasis[J]. Genes & Diseases, 2022,9(2). DOI： 10.1016/j.gendis.2021.04.006.

Samuel Shin, Cliff-Lawrence Ibeh, Eugenia Awuah Boadi, et al. Hypercalciuria switches Ca2+ signaling in proximal tubular cells, induces oxidative damage to promote calcium nephrolithiasis[J]. Genes & Diseases, 2022,9(2). DOI： 10.1016/j.gendis.2021.04.006.

摘要

Abstract

Proximal tubule (PT) transports most of the renal Ca

which was usually described as paracellular (passive). We found a regulated Ca

entry pathway in PT cells via the apical transient receptor potential canonical 3 (TRPC3) channel

which initiates transcellular Ca

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

]

further in

TRPC3

−/−

mice for developing such mixed stones to understand the mechanistic role of PT-Ca

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

entry from receptor-operated to store-operated pathway with a sustained rise in intracellular [Ca

] ([Ca

]

)

indicating the stagnation in PT Ca

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

due to escalation of hypercalciuria in TRPC3 ablated mice induced surplus CaP crystal formation and caused stagnation of PT [Ca

]

invoking PT cell injury

hence mixed stone formation.

关键词

Keywords

ApoptosisCa2+signalingCalcium nephrolithiasisChronic kidney diseaseFibrosisHypercalciuriaInflammationOxidative stress

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