Division of Nephrology, Department of Medicine, Fu Jen Catholic University Hospital, New Taipei 24352, Taiwan.
School of Medicine, Fu Jen Catholic University, New Taipei 242062, Taiwan.
Int J Mol Sci. 2021 Jun 8;22(12):6204. doi: 10.3390/ijms22126204.
Inflammation worsens oxalate nephropathy by exacerbating tubular damage. The transient receptor potential vanilloid 1 (TRPV1) channel is present in kidney and has a polymodal sensing ability. Here, we tested whether TRPV1 plays a role in hyperoxaluria-induced renal inflammation. In TRPV1-expressed proximal tubular cells LLC-PK, oxalate could induce cell damage in a time- and dose-dependent manner; this was associated with increased arachidonate 12-lipoxygenase (ALOX12) expression and synthesis of endovanilloid 12()-hydroxyeicosatetraenoic acid for TRPV1 activation. Inhibition of ALOX12 or TRPV1 attenuated oxalate-mediated cell damage. We further showed that increases in intracellular Ca and protein kinase C α activation are downstream of TRPV1 for NADPH oxidase 4 upregulation and reactive oxygen species formation. These trigger tubular cell inflammation via increased NLR family pyrin domain-containing 3 expression, caspase-1 activation, and interleukin (IL)-1β release, and were alleviated by TRPV1 inhibition. Male hyperoxaluric rats demonstrated urinary supersaturation, tubular damage, and oxidative stress in a time-dependent manner. Chronic TRPV1 inhibition did not affect hyperoxaluria and urinary supersaturation, but markedly reduced tubular damage and calcium oxalate crystal deposition by lowering oxidative stress and inflammatory signaling. Taking all these results together, we conclude that TRPV1 hyperfunction contributes to oxalate-induced renal inflammation. Blunting TRPV1 function attenuates hyperoxaluric nephropathy.
炎症通过加重肾小管损伤使草酸肾病恶化。瞬时受体电位香草醛 1 (TRPV1) 通道存在于肾脏中，具有多模式感应能力。在这里，我们测试 TRPV1 是否在高草酸尿引起的肾脏炎症中发挥作用。在 TRPV1 表达的近端肾小管细胞 LLC-PK 中，草酸盐可以时间和剂量依赖的方式诱导细胞损伤；这与花生四烯酸 12-脂氧合酶 (ALOX12) 表达增加和内香草素 12()-羟二十碳四烯酸(endovanilloid 12()-hydroxyeicosatetraenoic acid)的合成有关，后者可激活 TRPV1。ALOX12 或 TRPV1 的抑制可减轻草酸盐介导的细胞损伤。我们进一步表明，TRPV1 下游的细胞内 Ca 增加和蛋白激酶 C α 激活上调 NADPH 氧化酶 4 和活性氧的形成。这些通过增加 NLR 家族包含 pyrin 结构域的 3 表达、半胱天冬酶-1 激活和白细胞介素 (IL)-1β 的释放，触发肾小管细胞炎症，并通过 TRPV1 抑制得到缓解。雄性高草酸尿大鼠在时间依赖性方式下表现出尿过饱和度、肾小管损伤和氧化应激。慢性 TRPV1 抑制不会影响高草酸尿和尿过饱和度，但通过降低氧化应激和炎症信号显著减少肾小管损伤和草酸钙晶体沉积。综上所述，我们得出结论，TRPV1 功能亢进导致草酸诱导的肾脏炎症。阻断 TRPV1 功能可减轻高草酸尿肾病。
