慢性代謝性酸血症對腎臟腎素-血管緊縮素-醛固酮系統及紅血球生成素合成的影響

背景：代謝性酸血症是許多種疾病的併發症，包括敗血症、腎小管酸中毒及慢性腎病變等。雖然病人酸中毒的程度不同，就算病況輕微，但是「持續性」代謝性酸血症的影響的範圍卻可能十分廣泛而嚴重的。代謝性酸血症會引起系統性腎素-血管緊縮素-醛固酮系統（RAS）的活化，但是對腎臟內RAS造成的影響仍有待證實。而組織內RAS的活性才是決定器官是否受到傷害的真正因子，另外，酸血症對腎臟合成紅色球生成素（EPO）機制也未明。因此，本實驗主要目的在於探討當健康腎臟面臨過多的酸負荷時其組織內RAS活化及EPO合成的影響。方法：給予200至250克重的雄性Sprague-Dawley大鼠飲用含有0.14M NH4Cl 的水，分別第一或第八週後收集24小時的尿液後犧牲動物，對照組的老鼠飲用一般的去離子水。實驗結束時，由下腔靜脈抽取血液並摘取腎臟組織以進行多項的RAS成份及EPO基因表現分析。RAS成份的檢測包括腎素、腎素/原腎素接受器、血管緊縮素原肽、血管緊縮素轉換酶（ACE）、血管緊縮素第一及第二型接受器（AT1R及AT2R），此外，我們也分析EPO在腎臟內的表現及血中的濃度。結果：飲用NH4Cl的老鼠在一週時血中的pH值及重碳酸根濃度比對照組呈現有意義的降低，但在八週的老鼠卻仍能維持正常的酸鹼值。血中的鈣及鈉皆未改變但24小時的尿鈣及尿磷在實驗組都增加。此外，實驗組也出現較嚴重的蛋白尿（對照組vs 一週vs八週實驗組：2.49 ± 1.07 mg/100g vs. 6.78 ± 2.03 mg/100g vs. 5.68 ± 1.40 mg/100g，p值皆 <0.05)。在一週老鼠的腎臟內，多項的RAS分子都被活化，這包括angiotensinogen (359.6 ± 62.4% of control)、ACE (577.8 ± 107.3%)、AT1R (194.1 ± 25.2%) 及 AT2R (4629.4 ± 1525.5%，以上p值皆<0.05)。EPO的基因表現也增加(4356.5 ± 1695.5%)，但血清中的EPO濃度及血色素卻反而下降。八週的實驗組的AT1R表現仍持續增加（168.1 ± 12.7%，p<0.05），血清中的EPO濃度也下降。結論：過多的酸攝取會導致尿中鈣及磷的流失並且增加蛋白尿及造成腎臟的受損，而腎臟的變化可能和腎臟內的RAS活化有關。此外，代謝性酸血症增加腎臟EPO的表現的同時卻也造成血中EPO濃度減少及產生貧血現象。

關鍵字

腎素-血管緊縮素系統；慢性代謝性酸血症；紅血球生成素；腎臟受損

並列摘要

Background: Chronic metabolic acidosis is a common metabolic disturbance and its clinical impact can be severe and extensive. The role of intrarenal renin-angiotensin system (RAS) during metabolic acidosis is uncertain and how acidosis affects renal erythropoietin (EPO) synthesis remains unclear. The present study aimed to investigate intrarenal RAS and EPO synthesis in rats with excessive acid loading. Methods: Male Sprague-Dawley rats were fed on water containing 0.14M NH4Cl to induce metabolic acidosis. At 1 and 8 week interval, daily urine was collected for biochemical analysis and the experimental animals were harvested for blood sampling and renal tissue isolation. Gene expression analysis of RAS components, including renin, rennin/prorenin receptor, angiotensinogen, converting enzyme (ACE), angiotesin II type 1 and 2 receptor (AT1R/AT2R) and EPO was assessed by RT-PCR. Protein abundance was confirmed by Western-blot test and serum EPO concentration was determined. Results: Lower blood pH and bicarbonate concentration were found in 1 week NH4Cl treated rats but not in 8 weeks treatment group. There was an increased daily proteinuria in acid loaded rats (2.49 ± 1.07 mg/100g vs. 6.78 ± 2.03 mg/100g of 1 week group; 5.68 ± 1.40 mg/100g of 8 weeks group, both p<0.05) as well as significant hypercalciuria and hyperphosphaturia. In 1 week acidotic rats, significant upregulation of angiotensinogen (359.6 ± 62.4% of control), ACE (577.8 ± 107.3%), AT1R (194.1 ± 25.2%) and AT2R (4629.4 ± 1525.5%) were found. EPO gene expression was also upregulated (4356.5 ± 1695.5%, all p<0.05) in 1 week acid loaded rats. But both serum EPO and hemoglobin levels were decreased. In 8 weeks group, a significant increased AT1R expression was observed. Conclusion: Metabolic acidosis induced proteinuria in association with activation of intrarenal RAS and upregulation of EPO gene expression. In contrast, metabolic acidosis caused anemia and reduced serum EPO concentration. Our study provided valuable information about the pathophysiological change during excessive acid loading.

並列關鍵字

renin-angiotensin system ； metabolic acidosis ； erythropoietin ； kidney injury

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慢性代謝性酸血症對腎臟腎素-血管緊縮素-醛固酮系統及紅血球生成素合成的影響

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