The aging kidney: mechanisms of tubular regeneration

与大多数器官的情况相似，肾脏的功能随着年龄的增长而下降。在过去的几年里，在肾脏老化方面的科学兴趣主要集中在肾小球上。因此，肾小球滤过率在衰老过程中下降;这种肾功能的丧失早在生命的第40年就开始了。相反，对管状系统的老化知之甚少。因此，我们的治疗干预选择仍然有限。然而，随着年龄的增长，肾小管系统的功能下降。因此，老年人的集中能力和盐运输能力降低。这种肾小管功能的丧失在大多数情况下临床上并不明显。然而，一旦额外的风险因素影响肾功能，肾小管系统有限的再生能力就变得与临床相关。由于肾脏再生能力有限，慢性肾脏疾病的特征是肾功能逐渐和不可逆的下降。在基线时，肾小管上皮细胞的有丝分裂周转率低。尽管如此，显然有一些有丝分裂活动，但其调节机制仍然不清楚。此外，目前还不清楚肾小管系统的再生能力是否会随着年龄的增长而下降。本项目的目标是确定具有再生能力的肾小管细胞的特征，并了解健康肾脏中肾小管再生的动力学和定位。此外，我们的目标是了解调节有丝分裂的潜在机制，并评估干预策略，通过刺激内源性修复机制来保护肾小管功能。最后，我们将阐明健康肾脏中肾小管再生的机制与促进急性和慢性肾脏疾病损伤（部分）恢复的机制之间是否存在重叠。为了实现这些目标，我们将在小鼠中采用连续的活体双光子显微镜。总之，我们的研究将为我们理解肾小管系统的老化机制及其再生和功能保护提供相当大的进展。

Similar to the situation in most organs, the function of the kidney declines with age. During the last years, the scientific interest in terms of the aging of the kidney was predominately focused on the glomerulus. Thus, the glomerular filtration rate declines during aging; this loss of renal function starts as early as in the 4th decade of life. Conversely, relatively little is known about the aging of the tubular system. Consequently, our options for therapeutic interventions remain limited. Nevertheless, the function of the tubular system declines with aging. Thus, the concentrating ability and the salt transport capacity are reduced in elderly people. This loss of tubular function remains clinically inconspicuous in most cases. However, once additional risk factors impinge on kidney function, the limited regenerative capacity of the tubular system becomes clinically relevant. As a consequence of the limited kidney regenerative capacity, chronic kidney disease is characterized by a gradual and irreversible decline in renal function.At baseline, the mitotic turnover of the cells of the tubular epithelium is low. Nevertheless, there is apparently some mitotic activity, but the mechanisms of its regulation remain obscure. Furthermore, it is unknown if the regenerative capacity of the tubular system declines with age.The goal of this project is to determine the characteristics of tubular cells with regenerative capacity, and to understand the kinetics and localization of tubular regeneration in the healthy kidney. Furthermore, we aim to understand the underlying mechanisms of regulated mitosis and to assess strategies of interventions to conserve the tubular function by the means of stimulation of endogenous repair mechanisms. Finally, we will clarify if there is an overlap between the mechanisms that account for tubular regeneration in the healthy kidney with the mechanisms that facilitate a (partly) recovery from insults during acute and chronic kidney disease.To achieve these goals we will employ serial intravital two-photon microscopy in mice.In summary, our project will provide considerable progress for our understanding of the mechanisms of the aging of the tubular system and its regeneration and functional conservation.