Mechanism of Renal Injury Induced by Metabolic Factors and Prevention of the Injury by Vasoprotective Factors.

■低钾血症肾病(1)我们证明了低钾血症肾病大鼠的皮质和髓质中内皮素(ET)-1的产生上调，以及髓质中ETA型受体（ETA）和B型受体（ETB）的表达增加。ETA阻断可改善低钾血症肾病的肾小管间质损伤和肾功能。ETA阻断可改善肾脏ET-1的产生。相比之下，ETB阻断抑制肾ET-1的产生和ETA表达，改善低钾血症肾病肾小管间质损伤和肾ET-1的产生和ETA表达，改善肾小管间质损伤和肾功能。这些结果表明，ET-1不仅可以通过直接激活ETA，还可以通过ETB刺激局部产生ET-1来诱导肾损伤。(2)我们还证明了血管紧张素II拮抗剂可以改善低钾血症肾病的小管间质损伤和肾功能，并提示肾血管紧张素II的产生可能参与了低钾血症小管间质损伤的发病机制。■血管活性因子对肾的保护作用：肾上腺髓质素是一种有效的血管舒张肽和促血管细胞存活因子，可能通过抑制肾脏产生TNF-α和白细胞介素-6来改善肾缺血再灌注损伤中的肾小管坏死和细胞凋亡。■寻找糖尿病肾病的新候选基因：我们发现与2型糖尿病模型db/db小鼠肾脏发育、足细胞结构、糖脂代谢和氧化应激相关基因的表达与对照组相比发生了变化。这种改变可能与早期糖尿病肾小球病变的发病机制有关。

■Hypokalemic Nephropathy(1)We demonstrated an up-regulation of endothelin (ET)-1 production in the cortex and medulla, and an increase in the expression of the ET type A receptor (ETA) and type B receptor (ETB) in the medulla of rats with hypokalemic nephropathy. ETA blockade ameliorated renal tubulointerstitial injury and renal function in hypokalemic nephropathy. ETA blockade ameliorated renal ET-1 production. By contrast, ETB blockade suppressed renal ET-1 production and ETA expression as well as improved renal tubulointerstitial injury and renal ET-1 production and ETA expression as well as improved renal tubulointerstitial injury and renal function in hypokalemic nephropathy. These results suggested that ET-1 can induce renal injury not only via direct activation of ETA, but also by stimulating local production of ET-1 via ETB.(2)We also demonstrated that angiotensin II antagonism ameliorates tubulointerstitial injury and renal function in hypokalemic nephropathy, and suggested that renal angiotensin II generation may contribute to the pathogenesis of hypokalemic tubulointerstitial injury.■Renoprotection by Vasoactive Factors : Adrenomedullin, a potent vasorelaxing peptide and a prosurvival factor for vascular cells, ameliorates tubular necrosis and apoptosis in ischemic reperfusion injury of the kidney possibly by suppressing renal production of TNF-α and interleukin-6.■Searching New Candidate Genes for Diabetic Nephropathy : We found an alteration in the expression of genes related to kidney development and podocyte structure as well as glucose and lipid metabolism and oxidative stress in db/db mice, a model of type 2 diabetes, when compared to the control. This alteration might be related to pathogenesis of early diabetic glomerulopathy.