急性腎臟損傷因內質網壓力和粒線體動態平衡失衡而導致

Abstract

急性腎臟損傷是一種全身發炎反應症候群，加護病房的病人中, 80%的病人會發生急性腎臟損傷，死亡率約50%。因為致病機制還不清楚，還無法有效的治療。最近的研究發現TUDCA可以有效的抑制由脂多醣所引起的急性腎臟損傷。我們的研究主要想找出小鼠注射脂多醣後引起的急性腎臟損傷的機制，並找出有效的治療方式。 小鼠出生10周後分成三組，第一組為對照組，第二組為小鼠注射脂多醣 (8 mg/kg)，第三組為小鼠先注射TUDCA (500 mg/kg) 再注射脂多醣，注射脂多糖48小時後，犧牲小鼠並收集小鼠的血液、組織，進行生化分析，探討其致病機制。 小鼠注射脂多醣48小時後，測定血液中的葡萄糖、三酸甘油酯和膽固醇，確認是否成功誘發急性腎臟損傷。萃取小鼠腎臟mRNA和蛋白質，進行生化分析後，發現急性腎臟損傷會增加內質網壓力相關因子BIP和CHOP的表現量，也會增加發炎因子TNF-α和IL-6的表現量。粒線體動態平衡中，急性腎臟損傷與粒線體融合較無關，而粒線體分裂相關的因子DRP1和FIS1的表現量會增加，急性腎臟損傷也會使腎臟細胞纖維化，造成肺和腎臟的細胞嚴重損傷和出血。小鼠先注射TUDCA再注射脂多醣，可以有效抑制小鼠因為脂多醣而造成的急性腎臟損傷。 因此我們推論由脂多糖誘導的急性腎臟損傷是透過內質網壓力和粒線體動態平衡失衡而造成。

Acute kidney injury (AKI) is a serious complication of systemic inflammatory response syndrome. Although therapy for AKI has improved in recent years, AKI is still highly prevalent, especially in critically ill patients in the intensive care unit (ICU). AKI in the ICU has high mortality rates, reaching 80%. Tauroursodeoxycholic Acid (TUDCA) is recently found to suppress lipopolysaccharide (LPS) - induced acute kidney injury. We studied the mechanism of the mice injection LPS cause acute kidney injury. Mice distributed into three groups. First group was control. The second group were injected with LPS (8 mg/kg). The third group were injected TUDCA (500 mg/kg) before LPS injection. Mice LPS-injection after 48 hours, mice sacrificed and collected blood and tissues. Mice LPS-injection after 48 hours, we detected serum glucose, triglyceride, and cholesterol to success LPS-induced acute kidney injury. We isolated mice kidney mRNA and protein. LPS-injected mice were increased ER stress marker BIP and CHOP expression, inflammatory cytokines TNF-α and IL-6 expression, and mitochondrial fission marker DRP1 and FIS1 expression. Mitochondrial fusion marker MFN1, MFN2, and OPA1 were no significant difference. TUDCA treatment suppressed this changes. LPS-induced acute kidney injury was associated with vacuolar degeneration and apoptosis of renal tubular cells. Injection TUDCA ameliorated LPS-induced acute kidney injury in WT mice and apoE mice. LPS modulate acute kidney injury through enhanced ER stress and mitochondrial dynamic.