Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, Madrid, Spain.
Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, Madrid, Spain; RICORS2040, Madrid, Spain.
Biochem Pharmacol. 2024 Jun;224:116203. doi: 10.1016/j.bcp.2024.116203. Epub 2024 Apr 12.
Acute kidney injury (AKI) is common in hospitalized patients and increases short-term and long-term mortality. Treatment options for AKI are limited. Gut microbiota products such as the short-chain fatty acid butyrate have anti-inflammatory actions that may protect tissues, including the kidney, from injury. However, the molecular mechanisms of tissue protection by butyrate are poorly understood. Treatment with oral butyrate for two weeks prior to folic acid-induced AKI and during AKI improved kidney function and decreased tubular injury and kidney inflammation while stopping butyrate before AKI was not protective. Continuous butyrate preserved the expression of kidney protective factors such as Klotho, PGC-1α and Nlrp6 which were otherwise downregulated. In cultured tubular cells, butyrate blunted the maladaptive tubular cell response to a proinflammatory milieu, preserving the expression of kidney protective factors. Kidney protection afforded by this continuous butyrate schedule was confirmed in a second model of nephrotoxic AKI, cisplatin nephrotoxicity, where the expression of kidney protective factors was also preserved. To assess the contribution of preservation of kidney protective factors to kidney resilience, recombinant Klotho was administered to mice with cisplatin-AKI and shown to preserve the expression of PGC-1α and Nlrp6, decrease kidney inflammation and protect from AKI. In conclusion, butyrate promotes kidney resilience to AKI and decreases inflammation by preventing the downregulation of kidney protective genes such as Klotho. This information may be relevant to optimize antibiotic management during hospitalization.
急性肾损伤（AKI）在住院患者中很常见，并且会增加短期和长期死亡率。AKI 的治疗选择有限。肠道微生物群产物，如短链脂肪酸丁酸盐，具有抗炎作用，可保护组织，包括肾脏免受损伤。然而，丁酸盐对组织的保护作用的分子机制还知之甚少。在叶酸诱导的 AKI 前和 AKI 期间进行为期两周的口服丁酸盐治疗可改善肾功能，减少肾小管损伤和肾脏炎症，而在 AKI 前停止丁酸盐治疗则没有保护作用。持续的丁酸盐可保留 Klotho、PGC-1α 和 Nlrp6 等肾脏保护因子的表达，否则这些因子会下调。在培养的肾小管细胞中，丁酸盐减轻了适应性不良的肾小管细胞对促炎环境的反应，从而保留了肾脏保护因子的表达。这种连续丁酸盐方案在另一种肾毒性 AKI 模型——顺铂肾毒性中得到了证实，其中肾脏保护因子的表达也得到了保留。为了评估保护肾脏保护因子对肾脏恢复能力的贡献，向顺铂-AKI 小鼠给予重组 Klotho，并显示出保留 PGC-1α 和 Nlrp6 的表达、减少肾脏炎症和预防 AKI 的作用。总之，丁酸盐通过防止 Klotho 等肾脏保护基因的下调，促进 AKI 后肾脏的恢复能力并减少炎症。这些信息可能与优化住院期间抗生素管理有关。
