Pittock Siobhan T, Norby Suzanne M, Grande Joseph P, Croatt Anthony J, Bren Gary D, Badley Andrew D, Caplice Noel M, Griffin Matthew D, Nath Karl A
Department of Pediatric and Adolescent Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota 55905, USA.
Kidney Int. 2005 Aug;68(2):611-22. doi: 10.1111/j.1523-1755.2005.00439.x.
Up-regulation of heme oxygenase-1 (HO-1) occurs in, and often confers protection to, the injured kidney. Up-regulation of monocyte chemoattractant protein-1 (MCP-1) promotes not only acute and chronic nephritides but also acute ischemic and nephrotoxic injury. The present study was stimulated by the hypothesis that expression of MCP-1 is suppressed by HO-1, and analyzed the effect of HO-1 on the expression of MCP-1 in stressed and unstressed conditions.
Expression of MCP-1 and pathophysiologic correlates were examined in HO-1 knockout (HO-1-/-) and wild-type (HO-1+/+) mice in the unstressed state in young and aged mice, and following nephrotoxic and ischemic insults.
In unstressed HO-1-/- mice, plasma levels of MCP-1 protein were elevated, and MCP-1 mRNA expression was increased in circulating leukocytes and in the kidney. Such early and heightened up-regulation of MCP-1 was eventually accompanied by phenotypic changes in the aged kidney consistent with MCP-1, namely, proliferative changes in glomeruli, tubulointerstitial disease, and up-regulation of transforming growth factor-beta1 (TGF-beta1) and collagens I, III, and IV. In response to a nephrotoxic insult such as hemoglobin, MCP-1 mRNA was up-regulated in a markedly sustained manner in HO-1-/- mice. In response to a duration of ischemia that exerted little effect in HO-1+/+ mice, HO-1-/- mice exhibited higher expression of MCP-1 mRNA, enhanced activation of nuclear factor-kappaB (NF-kappaB) (the transcription factor that regulates MCP-1), markedly greater functional and structural renal injury, increased caspase-3 expression, and increased mortality.
In the absence of HO-1, expression of MCP-1 is significantly and consistently enhanced in unstressed and stressed conditions. We speculate that the protective effects of HO-1 in injured tissue may involve, at least in part, the capacity of HO-1 to restrain up-regulation of MCP-1.
血红素加氧酶-1（HO-1）的上调出现在受损肾脏中，并常常赋予其保护作用。单核细胞趋化蛋白-1（MCP-1）的上调不仅会促进急性和慢性肾炎，还会导致急性缺血性和肾毒性损伤。本研究受MCP-1的表达受HO-1抑制这一假说的启发，分析了HO-1在应激和非应激条件下对MCP-1表达的影响。
在年轻和老年小鼠的非应激状态下，以及在肾毒性和缺血性损伤后，检测HO-1基因敲除（HO-1-/-）和野生型（HO-1+/+）小鼠中MCP-1的表达及病理生理相关性。
在非应激的HO-1-/-小鼠中，血浆MCP-1蛋白水平升高，循环白细胞和肾脏中的MCP-1 mRNA表达增加。MCP-1这种早期且增强的上调最终伴随着老年肾脏中与MCP-1一致的表型变化，即肾小球增殖性变化、肾小管间质疾病，以及转化生长因子-β1（TGF-β1）和I、III、IV型胶原的上调。在受到如血红蛋白等肾毒性损伤时，HO-1-/-小鼠中的MCP-1 mRNA以明显持续的方式上调。在对HO-1+/+小鼠影响较小的一段缺血时间后，HO-1-/-小鼠表现出更高的MCP-1 mRNA表达、增强的核因子-κB（NF-κB）（调节MCP-1的转录因子）激活、明显更严重的功能性和结构性肾损伤、caspase-3表达增加以及死亡率升高。
在缺乏HO-1的情况下，MCP-1的表达在非应激和应激条件下均显著且持续增强。我们推测HO-1在受损组织中的保护作用可能至少部分涉及HO-1抑制MCP-1上调的能力。
