Laboratorio di Biochimica Analitica e Proteomica, Centro Scienze dell'Invecchiamento e Medicina Traslazionale - CeSI-MeT, Via Luigi Polacchi 11, 66100, Chieti, Italy.
Department of Medical, Oral and Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini 29, 66013, Chieti, Italy.
Acta Diabetol. 2018 Feb;55(2):121-129. doi: 10.1007/s00592-017-1074-y. Epub 2017 Nov 13.
The tissue inhibitor of metalloproteinase TIMP3 is a stromal protein that restrains the activity of both protease and receptor in the extracellular matrix and has been found to be down-regulated in diabetic nephropathy (DN), the leading cause of end-stage renal disease in developed countries.
In order to gain deeper insights on the association of loss of TIMP3 and DN, we performed differential proteomic analysis of kidney and blood metabolic profiling of wild-type and Timp3-knockout mice before and after streptozotocin (STZ) treatment, widely used to induce insulin deficiency and hyperglycemia.
Kidney proteomic data and blood metabolic profiles suggest significant alterations of peroxisomal and mitochondrial fatty acids β-oxidation in Timp3-knockout mice compared to wild-type mice under basal condition. These alterations were exacerbated in response to STZ treatment.
Proteomic and metabolomic approaches showed that loss of TIMP3 alone or in combination with STZ treatment results in significant alterations of kidney lipid metabolism and peripheral acylcarnitine levels, supporting the idea that loss of TIMP3 may generate a phenotype more prone to DN.
金属蛋白酶组织抑制剂 TIMP3 是一种基质蛋白，可抑制细胞外基质中蛋白酶和受体的活性，在糖尿病肾病 (DN) 中发现其下调，DN 是发达国家终末期肾病的主要原因。
为了更深入地了解 TIMP3 缺失与 DN 的关联，我们对野生型和 Timp3 基因敲除小鼠在链脲佐菌素 (STZ) 处理前后的肾脏进行了差异蛋白质组学分析，并对血液代谢物进行了分析，STZ 广泛用于诱导胰岛素缺乏和高血糖。
与野生型小鼠相比，Timp3 基因敲除小鼠的肾脏蛋白质组学数据和血液代谢物图谱表明，在基础条件下，过氧化物酶体和线粒体脂肪酸β氧化存在显著改变。这些改变在 STZ 处理后加剧。
蛋白质组学和代谢组学方法表明，TIMP3 缺失单独或与 STZ 处理相结合会导致肾脏脂质代谢和外周酰基辅酶 A 水平的显著改变，支持了 TIMP3 缺失可能产生更易发生 DN 的表型的观点。
