Abstract
BackgroundThe molecular mechanisms that mediate the ischemia-reperfusion (I/R) injury in kidney are not completely understood. It is also largely unknown whether such mechanisms overlap with those governing the early development of kidney.Methodology/Principal FindingsWe performed gene expression analysis to investigate the transcriptome changes during regeneration after I/R injury in the rat (0 hr, 6 hr, 24 hr, and 120 hr after reperfusion) and early development of mouse kidney (embryonic day 16 p.c. and postnatal 1 and 7 day). Pathway analysis revealed a wide spectrum of molecular functions that may participate in the regeneration and developmental processes of kidney as well as the functional association between them. While the genes associated with cell cycle, immunity, inflammation, and apoptosis were globally activated during the regeneration after I/R injury, the genes encoding various transporters and metabolic enzymes were down-regulated. We also observed that these injury-associated molecular functions largely overlap with those of early kidney development. In particular, the up-regulation of kinases and kinesins with roles in cell division was common during regeneration and early developmental kidney as validated by real-time PCR and immunohistochemistry.ConclusionsIn addition to the candidate genes whose up-regulation constitutes an overlapping expression signature between kidney regeneration and development, this study lays a foundation for studying the functional relationship between two biological processes.
Highlights
Acute kidney injury represents a common clinical problem leading to high rates of morbidity and mortality [1]
Kidney injury was induced by 20 minutes of bilateral renal ischemia followed by reperfusion that resulted in kidney dysfunction, characterized by elevation of serum creatinine (SCr) and blood urea nitrogen (BUN), (Figure 1A and 1B) at 24 hr of reperfusion followed by a recovery at 120 hr
The histopathological examination showed typical lesions caused by renal ischemia at 24 hr characterized by proximal tubular necrosis and apoptosis that resulted in substantial loss in epithelial brush border and cell debris accumulation in luminal area at 24 hr with a structural and functional recovery by 120 hr due to an efficient kidney regeneration response (Figure 2A)
Summary
Acute kidney injury represents a common clinical problem leading to high rates of morbidity and mortality [1]. I/R injury may recapitulate those of kidney organogenesis in which the kidney injury induces the re-expression of various nephrogenic genes such as Vimentin, Pax-2 and Bmp-7 [8,9,10] Considering that these two biological processes (kidney regeneration and development) require tightly regulated cellular processes that control cell proliferation and differentiation, a comparison between the transcriptional programs associated with these processes may provide a better understanding about the underlying molecular mechanisms, as exemplified in other organogenesis model (e.g., liver) [11,12]. The molecular mechanisms that mediate the ischemia-reperfusion (I/R) injury in kidney are not completely understood It is largely unknown whether such mechanisms overlap with those governing the early development of kidney
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