Roncal-Jimenez Carlos A, Ishimoto Takuji, Lanaspa Miguel A, Milagres Tamara, Hernando Ana Andres, Jensen Thomas, Miyazaki Makoto, Doke Tomohito, Hayasaki Takahiro, Nakagawa Takahiko, Marumaya Shoichi, Long David A, Garcia Gabriela E, Kuwabara Masanari, Sánchez-Lozada Laura G, Kang Duk-Hee, Johnson Richard J
Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado;
Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado; Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Am J Physiol Renal Physiol. 2016 Oct 1;311(4):F722-F730. doi: 10.1152/ajprenal.00306.2016. Epub 2016 Jul 27.
Aging-associated kidney disease is usually considered a degenerative process associated with aging. Recently, it has been shown that animals can produce fructose endogenously, and that this can be a mechanism for causing kidney damage in diabetic nephropathy and in association with recurrent dehydration. We therefore hypothesized that low-level metabolism of endogenous fructose might play a role in aging-associated kidney disease. Wild-type and fructokinase knockout mice were fed a normal diet for 2 yr that had minimal (<5%) fructose content. At the end of 2 yr, wild-type mice showed elevations in systolic blood pressure, mild albuminuria, and glomerular changes with mesangial matrix expansion, variable mesangiolysis, and segmental thrombi. The renal injury was amplified by provision of high-salt diet for 3 wk, as noted by the presence of glomerular hypertrophy, mesangial matrix expansion, and alpha smooth muscle actin expression, and with segmental thrombi. Fructokinase knockout mice were protected from renal injury both at baseline and after high salt intake (3 wk) compared with wild-type mice. This was associated with higher levels of active (phosphorylated serine 1177) endothelial nitric oxide synthase in their kidneys. These studies suggest that aging-associated renal disease might be due to activation of specific metabolic pathways that could theoretically be targeted therapeutically, and raise the hypothesis that aging-associated renal injury may represent a disease process as opposed to normal age-related degeneration.
衰老相关的肾脏疾病通常被认为是一种与衰老相关的退行性过程。最近，研究表明动物能够内源性产生果糖，并且这可能是导致糖尿病肾病以及与反复脱水相关的肾脏损伤的一种机制。因此，我们推测内源性果糖的低水平代谢可能在衰老相关的肾脏疾病中起作用。将野生型和果糖激酶基因敲除小鼠喂食果糖含量极低（<5%）的正常饮食2年。在2年结束时，野生型小鼠出现收缩压升高、轻度蛋白尿以及肾小球改变，伴有系膜基质扩张、不同程度的系膜溶解和节段性血栓形成。如通过肾小球肥大、系膜基质扩张、α平滑肌肌动蛋白表达以及节段性血栓形成所观察到的，给予3周高盐饮食会加重肾脏损伤。与野生型小鼠相比，果糖激酶基因敲除小鼠在基线时以及高盐摄入（3周）后均受到肾脏损伤的保护。这与它们肾脏中活性（丝氨酸1177磷酸化）内皮型一氧化氮合酶水平较高有关。这些研究表明，衰老相关的肾脏疾病可能是由于特定代谢途径的激活，理论上这些途径可以作为治疗靶点，并且提出了衰老相关的肾脏损伤可能代表一种疾病过程而非正常的年龄相关退变的假说。
