Jensen Anja M, Li Chunling, Praetorius Helle A, Nørregaard Rikke, Frische Sebastian, Knepper Mark A, Nielsen Søren, Frøkiaer Jørgen
The Water and Salt Research Center, Univ. of Aarhus, Institute of Clinical Medicine/Dept. of Clinical Physiology, Aarhus Univ. Hospital, Brendstrupgaardsvej, DK-8200 Aarhus N., Denmark.
Am J Physiol Renal Physiol. 2006 Nov;291(5):F1021-32. doi: 10.1152/ajprenal.00387.2005. Epub 2006 Jun 6.
The renin-angiotensin system is well known to be involved in the pathophysiological changes in renal function after obstruction of the ureter. Previously, we demonstrated that bilateral ureteral obstruction (BUO) is associated with dramatic changes in the expression of both renal sodium transporters and aquaporin water channels (AQPs). We now examined the effects of the AT(1)-receptor antagonist candesartan on the dysregulation of AQPs and key renal sodium transporters in rats subjected to 24-h BUO and followed 2 days after release of BUO (BUO-2R). Consistent with previous observations, BUO-2R resulted in a significantly decreased expression of AQP1, -2, and -3 compared with control rats. Concomitantly, the rats developed polyuria and reduced urine osmolality. Moreover, expression of the type 2 Na-phosphate cotransporter (NaPi-2) and type 1 bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) was markedly reduced, consistent with postobstructive natriuresis. Candesartan treatment from the onset of obstruction attenuated the reduction in GFR (3.1 +/- 0.4 vs. 1.7 +/- 0.3 ml.min(-1).kg(-1)) and partially prevented the reduction in the expression of AQP2 (66 +/- 21 vs. 13 +/- 2%, n = 7; P < 0.05), NaPi-2 (84 +/- 6 vs. 57 +/- 10%, n = 7; P < 0.05), and NKCC2 (89 +/- 12 vs. 46% +/- 11, n = 7; P < 0.05). Consistent with this, candesartan treatment attenuated the increase in urine output (58 +/- 4 vs. 97 +/- 5 microl.min(-1).kg(-1), n = 7; P < 0.01) and the reduction in sodium reabsorption (433 +/- 62 vs. 233 +/- 45 micromol.min(-1).kg(-1), n = 7; P < 0.05) normally found in rats subjected to BUO. Moreover, candesartan treatment attenuated induction of cyclooxygenase 2 (COX-2) expression in the inner medulla, suggesting that COX-2 induction in response to obstruction is regulated by ANG II. In conclusion, candesartan prevents dysregulation of AQP2, sodium transporters, and development of polyuria seen in BUO. This strongly supports the view that candesartan protects kidney function in response to urinary tract obstruction.
众所周知，肾素 - 血管紧张素系统参与输尿管梗阻后肾功能的病理生理变化。此前，我们证明双侧输尿管梗阻（BUO）与肾钠转运体和水通道蛋白水通道（AQP）表达的显著变化有关。我们现在研究了AT(1)受体拮抗剂坎地沙坦对24小时BUO大鼠及解除梗阻后2天（BUO - 2R）时AQP和关键肾钠转运体失调的影响。与之前的观察结果一致，与对照大鼠相比，BUO - 2R导致AQP1、 - 2和 - 3的表达显著降低。同时，大鼠出现多尿和尿渗透压降低。此外，2型钠 - 磷酸盐共转运体（NaPi - 2）和1型布美他尼敏感的钠 - 钾 - 2氯共转运体（NKCC2）的表达明显降低，这与梗阻后利尿一致。从梗阻开始就给予坎地沙坦治疗可减轻肾小球滤过率的降低（3.1±0.4 vs. 1.7±0.3 ml·min⁻¹·kg⁻¹），并部分预防AQP2（66±21 vs. 13±2%，n = 7；P < 0.05）、NaPi - 2（84±6 vs. 57±10%，n = 7；P < 0.05）和NKCC2（89±12 vs. 46%±11，n = 7；P < 0.05）表达的降低。与此一致，坎地沙坦治疗减轻了尿量的增加（58±4 vs. 97±5 μl·min⁻¹·kg⁻¹，n = 7；P < 0.01）和钠重吸收的降低（433±62 vs. 233±45 μmol·min⁻¹·kg⁻¹，n = 7；P < 0.05），这在BUO大鼠中通常会出现。此外，坎地沙坦治疗减弱了内髓质中环氧化酶2（COX - 2）表达的诱导，表明对梗阻的COX - 2诱导是由血管紧张素II调节的。总之，坎地沙坦可预防BUO中出现的AQP2、钠转运体失调和多尿的发生。这有力地支持了坎地沙坦在应对尿路梗阻时保护肾功能的观点。
