Pathophysiological significance of the cell cycle in acute kidney injury

点击翻译按钮获取中文摘要

Acute kidney injury is a serious clinical condition in which kidney function declines abruptly and for which there is no specific therapy. In many cases, kidney function can recover, but permanent damage also occurs, leading to end stage renal disease. Whether kidney recovery is successful depends on several factors. One important component is tubular cell proliferation, which is usually considered to contribute to the repair of damaged renal tubules. However, in our preliminary work, we observed that damage-induced proliferation can be not only reparative but also detrimental. In transgenic mice specifically lacking the cell cycle protein cyclin D1 in the proximal tubule, we observed that reduced proliferative capacity protects the kidney. These findings fit with previous observations from other groups with pharmacological cell cycle inhibition. In the present application, we will investigate the underlying processes of this phenomenon and we will test whether the principle of cyclin D1 antagonization can be exploited therapeutically. To address the latter point, we will use an siRNA-based knockdown strategy in a mouse model that could allow for potential clinical translation. To address the question of the mechanistic basis, we performed transcriptome analyses in preliminary work in which we examined differences in proximal tubules with and without cyclin D1 ablation. In doing so, we were looking for an association of cyclin D1 with damage-aggravating transcripts. Indeed, we found transcriptional differences exclusively for cell cycle genes, so we assume that the protective mechanism arises directly from inhibition of cell cycle activation per se. As a crucial factor, we now want to test the 'cellular energy hypothesis', in which we postulate that cell cycle blockade is nephroprotective by protecting against excessive energy expenditure of cell cycle activation. We plan to test this hypothesis in cell culture experiments as well as in mouse and zebrafish embryos by using different damage models and proliferation interventions to analyze cell and tissue responses in response to cell cycle activation. To this end we will use energy carrier measurements, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry imaging (MALDI-TOF-MSI), and cellular damage analysis. Together, the expected results should help to better understand the role of tubular cell proliferation in acute renal failure. The long-term goal is to establish a basis that will allow the derivation of new therapeutic strategies.