Lu Chien-Lin, Tseng Yi-Shiou, Wu Wen-Bin, Liao Chun-Hou, Ma Ming-Chieh
School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei 242062, Taiwan.
Division of Nephrology, Department of Internal Medicine, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei 243089, Taiwan.
Antioxidants (Basel). 2025 Sep 5;14(9):1088. doi: 10.3390/antiox14091088.
Hydrogen sulfide (HS) exerts regulatory functions in kidney diseases. However, its protective role against kidney stone formation remains unclear. Here, we demonstrate that hyperoxaluria or oxalate exposure impairs HS formation, leading to tubular injury and calcium oxalate (CaOx) crystal deposition in both in vivo and in vitro models. In male rats fed 5% hydroxy-L-proline (HP), time-dependent increases in urinary supersaturation, tubular damage, and renal CaOx deposition were observed compared to controls. These changes were associated with the decreased expression of HS-producing enzymes and elevated urinary secretion of osteopontin (OPN) and Tamm-Horsfall protein (THP). Notably, the protein level and activity of specificity protein 1 (Sp1), a transcription factor regulating these enzymes, were markedly decreased in HP-treated kidneys. Chronic supplementation with the HS donor GYY4137 (GYY) significantly attenuated HP-induced tubular injury and CaOx deposition by reducing OPN and THP secretion. Consistent with in vivo results, HS donors mitigated oxalate-induced tubular cell damage and CaOx formation in MDCK cells. Mechanistically, oxalate activated cyclic AMP/protein kinase A (PKA) signaling, which promoted OPN and THP secretion; these effects were eradicated by the PKA inhibitor H89 or GYY. These findings indicate that hyperoxaluria impairs Sp1 transcriptional activity, resulting in HS deficiency and compromised anticrystallization defense in oxalate-induced tubulopathy.
硫化氢（HS）在肾脏疾病中发挥调节功能。然而，其对肾结石形成的保护作用仍不清楚。在此，我们证明高草酸尿症或草酸盐暴露会损害HS的形成，导致体内和体外模型中均出现肾小管损伤和草酸钙（CaOx）晶体沉积。在喂食5%羟基-L-脯氨酸（HP）的雄性大鼠中，与对照组相比，观察到尿过饱和度、肾小管损伤和肾脏CaOx沉积随时间增加。这些变化与产生HS的酶的表达降低以及骨桥蛋白（OPN）和Tamm-Horsfall蛋白（THP）的尿分泌增加有关。值得注意的是，在HP处理的肾脏中，作为调节这些酶的转录因子的特异性蛋白1（Sp1）的蛋白水平和活性显著降低。长期补充HS供体GYY4137（GYY）可通过减少OPN和THP分泌，显著减轻HP诱导的肾小管损伤和CaOx沉积。与体内结果一致，HS供体减轻了草酸盐诱导的MDCK细胞中的肾小管细胞损伤和CaOx形成。机制上，草酸盐激活环磷酸腺苷/蛋白激酶A（PKA）信号通路，促进OPN和THP分泌；PKA抑制剂H89或GYY消除了这些作用。这些发现表明，高草酸尿症损害Sp1转录活性，导致HS缺乏，并削弱了草酸盐诱导的肾小管病中的抗结晶防御。
