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1 Division of Nephrology, Fred Hutchinson Cancer Research Ctr, Seattle, Washington, United States
2 Clinical Division, Fred Hutchinson Cancer Research Center, seattle, Washington, United States
3 Research Pathology, Fred Hutchinson Cancer Research Center, seattle, Washington, United States
* To whom correspondence should be addressed. E-mail: dzager{at}fhcrc.org.
Background: Acute renal failure (ARF) induces tubular hyper-responsiveness to TLR4 ligands, culminating in exaggerated renal cytokine / chemokine production. However, the fate of TLR4 protein during acute tubular injury remains unknown. The study sought new insights into this issue. Methods: Male CD-1 mice were subjected to: i) unilateral ischemia / reperfusion (I/R), ii) cisplatin (CP) nephrotoxicity; or iii) glycerol- induced myohemoglobinuric ARF. Renal cortical TLR4 protein (Western blotting; immunohistochemistry), and TLR4 mRNA levels (RT-PCR) were determined thereafter (90 min - 4 days). Urinary TLR4 excretion post I/R or CP injection was also assessed. To gain proximal tubule specific results, TLR4 protein and mRNA were quantified in post hypoxic or oxidant (Fe) challenged isolated mouse tubules. Finally, TLR4 mRNA was determined in antimycin A- injured cultured proximal tubular (HK-2) cells. Results: Acute in vivo renal injury reduced proximal tubule TLR4 content. These changes corresponded with the appearance of TLR4 fragment(s) in urine, and a persistent increase in renal cortical TLR4 mRNA. Isolated proximal tubules responded to injury with rapid TLR4 reductions, extracellular TLR4 release, and increases in TLR4 mRNA. Glycine blocked these processes, implying membrane pore formation was involved. HK-2 cell injury increased TLR4 mRNA, but not protein, suggesting intact transcriptional, but not translational, pathways. Conclusion: Diverse forms of acute tubular injury rapidly reduce proximal tubular TLR4 content. Plasma membrane TLR4 release through glycine- suppressible pores, possibly coupled with a translation block, appear to be involved. Rapid post injury urinary TLR4 excretion suggests its utility as a 'biomarker' of impending ARF.
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