Hypercalciuria switches Ca^(2+) signaling in proximal tubular cells,induces oxidative damage to promote calcium nephrolithiasis  

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

机构地区：[1]Calcium Signaling Laboratory,Research Service,Veterans Affairs Medical Center,50 Irving Street,NW,Washington,DC 20422,USA

出　　处：《Genes & Diseases》2022年第2期531-548,共18页基因与疾病（英文）

基　　金：National Institute of Diabetes and Digestive and Kidney Diseases(No.DK102043)funding to B.C.B supported this study.

摘　　要：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.

关 键 词：Apoptosis Ca^(2+)þsignaling Calcium nephrolithiasis Chronic kidney disease FIBROSIS HYPERCALCIURIA Inflammation Oxidative stress 

分 类 号：R692[医药卫生—泌尿科学]