Mitochondrial-based Determinants of Sex Differences in Acute Kidney Injury

急性肾损伤(AKI)困扰着大量住院患者，尤其是那些危重患者。 生病了。由于在临床和动物模型中都观察到对雌性AKI的保护，这是一个更好的解释 对这种保护的潜在生物学机制的研究可能对为这两种疾病提供新颖、有效的干预至关重要 患有AKI的女性和男性。为了支持基于性别的对AKI的易感性，我们已经证明了雌性小鼠 与男性相比，接受顺铂诱导的AKI(CP)保留了肾功能 更糟糕的是AKI。女性对肾损伤的抵抗力的基础机制是清楚的 有可能阐明独特的病理机制，并代表着我们知识中的一个关键差距。 线粒体功能障碍一直被认为是AKI预后的一个因素，雌激素也会改变 线粒体生物能量学，可能是通过线粒体中可能存在的雌激素受体。首屈一指 线粒体功能在性别定义的易感性中的作用将在这项提案中通过研究一种新的 本研究所建立的小鼠线粒体-核交换(MNX)模型(目标1)。这些老鼠有 两种品系的小鼠之间的交换，使得MNX小鼠具有一种品系的核特征 小鼠和另一品系小鼠的线粒体特征。我们的初步数据表明， 在AKI的易感性方面，MNX小鼠的亲本品系具有不同的性别特征，这使得 在损伤模型中研究这些细胞器的影响。线粒体的第二次调制 功能将通过热中性进行检查，即在没有额外线粒体的环境温度下 为了保持核心体温，需要通过分流来产生热量。标准的温度是 通常在~22-23C(TS)，而啮齿类动物的温度中温为~30C(TT)。热中性度改变 其他器官系统的性别差异，但在AKI中尚未研究，将在这些研究中进行检验 (目标2)。服用雌激素或睾酮后线粒体功能改变的检测 调节对AKI的易感性尚未研究长期使用激素。长期执政 荷尔蒙，特别是反映变性人地位的跨性别给药，一直是 最低限度的研究，而且根本不在肾脏(目标3)。完整的总体假设是线粒体 生物能量学和动力学以性别特有的方式改变了对AKI的易感性。在确定性行为如何 差异是在这些不同的范式中调节的，这些研究将提供基线理解 需要更好地界定“女性AKI”，并确定可在干预措施中加以利用的细微差别。

Acute kidney injury (AKI) afflicts substantial numbers of hospitalized patients, particularly those who are critically ill. Because protection from AKI in females is observed both clinically and in animal models, a better elucidation of the underlying biology of this protection may be essential to providing novel, effective intervention to both females and males with AKI. In support of a sex-based susceptibility to AKI, we have shown that female mice undergoing cisplatin-induced AKI (CP) have preserved renal function compared to males, which have significantly worse AKI. Clarity in the mechanisms that underpin resistance of females to renal injury has the potential to illuminate unique pathological mechanisms and represents a critical gap in our knowledge. Mitochondrial dysfunction is noted consistently as a contributor to the outcomes of AKI, and estrogen alters mitochondrial bioenergetics, perhaps via estrogen receptors that may be present in mitochondria. The primacy of mitochondrial function in sex-defined susceptibility will be confirmed in this proposal by examining a novel mouse model, developed at our institution, of mitochondrial-nuclear exchange (MNX) (Aim 1). These mice have an exchange between two strains of mice such that the MNX mice have nuclear characteristics of one strain of mice and the mitochondrial characteristics of another strain of mice. Our preliminary data demonstrate that the parental strains of the MNX mice have different sex-based profiles in susceptibility to AKI allowing for the investigation of the influence of these organelles in an injury model. A second modulation of mitochondrial function will be examined with thermoneutrality, the ambient temperature at which no additional mitochondrial shunting to heat generation is required to maintain core body temperature. Standard vivarium temperatures are typically at ~22-23C (TS), while thermoneutral temperatures for rodents is ~30C (TT). Thermoneutrality alters sex-differences in other organ systems, but has not been studied in AKI and will be examined in these studies (Aim 2). Examination of changes in mitochondrial function with administration of estrogen or testosterone to modulate susceptibility to AKI have not investigated long-term hormone administration. Long-term administration of hormones, particularly cross-sex administration reflecting the status of transgender individuals, has been minimally studied, and not at all in the kidney (Aim 3). The integrated overall hypothesis is that mitochondrial bioenergetics and dynamics alters susceptibility to AKI in a sex-specific manner. In establishing how sex differences are modulated in these different paradigms, these studies will provide the baseline understanding needed to better define “female AKI” and determine nuanced differences that may be exploited in interventions.