The aging kidney: mechanisms of tubular regeneration

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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.