Department of Nephrology, Monash Medical Centre, 246 Clayton Road, Clayton, VIC 3168, Australia.
Am J Nephrol. 2011;34(4):337-46. doi: 10.1159/000331058. Epub 2011 Aug 26.
BACKGROUND/AIMS: The c-Jun amino-terminal kinase (JNK) signaling pathway is activated in human kidney diseases and promotes renal injury in experimental glomerulonephritis. In this study, we examined whether JNK signaling plays a role in the development of diabetic nephropathy or in regulating hypertension, which exacerbates diabetic renal injury.
Diabetes was induced in spontaneously hypertensive rats (SHR) using streptozotocin. At week 16 of diabetes, rats with equivalent hyperglycemia and albuminuria were randomized into groups which received no treatment, vehicle alone or a selective JNK inhibitor (CC-930, 60 mg/kg/bid) for 10 weeks. These rats were assessed for hypertension and progression of renal damage.
At week 16, diabetic rats showed increased kidney JNK activation compared with nondiabetic controls. Effective JNK inhibition was demonstrated at week 26 by reductions in c-Jun phosphorylation. CC-930 did not affect blood pressure, kidney hypertrophy, glomerular hyperfiltration, podocyte loss, glomerular fibrosis or tubulointerstitial injury in diabetic SHR. However, CC-930 reduced macrophages and ccl2 mRNA levels in diabetic kidneys. In contrast, CC-930 exacerbated albuminuria at week 26, which was associated with reduced glomerular mRNA levels of the podocyte-specific molecules, nephrin and podocin.
JNK inhibition does not prevent the progression of early diabetic renal injury in hypertensive rats, which contrasts with the ability of JNK inhibition to suppress albuminuria and injury in experimental glomerulonephritis.
背景/目的：c-Jun 氨基末端激酶（JNK）信号通路在人类肾脏疾病中被激活，并在实验性肾小球肾炎中促进肾脏损伤。在本研究中，我们研究了 JNK 信号通路是否在糖尿病肾病的发展中发挥作用，或者是否在调节高血压中发挥作用，因为高血压会加重糖尿病肾脏损伤。
使用链脲佐菌素诱导自发性高血压大鼠（SHR）发生糖尿病。在糖尿病 16 周时，将伴有等效高血糖和蛋白尿的大鼠随机分为未治疗组、单独给予载体组或选择性 JNK 抑制剂（CC-930，60mg/kg/次，每天 2 次）治疗 10 周。评估这些大鼠的高血压和肾脏损伤进展情况。
在 16 周时，与非糖尿病对照组相比，糖尿病大鼠的肾脏 JNK 激活增加。在 26 周时通过减少 c-Jun 磷酸化来证明有效的 JNK 抑制。CC-930 对糖尿病 SHR 的血压、肾脏肥大、肾小球高滤过、足细胞丢失、肾小球纤维化或肾小管间质损伤没有影响。然而，CC-930 降低了糖尿病肾脏中的巨噬细胞和 ccl2 mRNA 水平。相比之下，CC-930 在 26 周时加剧了白蛋白尿，这与肾小球特异性分子，nephrin 和 podocin 的 mRNA 水平降低有关。
JNK 抑制并不能预防高血压大鼠早期糖尿病肾脏损伤的进展，这与 JNK 抑制抑制实验性肾小球肾炎中的白蛋白尿和损伤的能力形成对比。
