Acquired resistance to rechallenge injury in rats that recovered from mild renal damage induced by uranyl acetate: accelerated proliferation and hepatocyte growth factor/c-Met axis
- First Online:
- 113 Downloads
Rats that recovered from mild proximal tubule (PT) injury without renal dysfunction by subtoxic insult, developed partial resistance to subsequent nephrotoxic insult. This partial resistance was associated with reduced renal dysfunction and accelerated PT cell proliferation compared with vehicle treatment as the first insult. Here we assessed the role and potential mechanisms of accelerated PT proliferation in this acquired resistance model.
Rats at 14 days after recovering from prior mild renal damage induced by 0.2 mg/kg uranyl acetate (UA) (subtoxic dose) were rechallenged with 4 mg/kg UA (nephrotoxic dose) to establish the acquired resistance model. Cell cycle was inhibited by colchicine to examine the contribution of accelerated PT cell proliferation evaluated by in vivo bromodeoxyuridine (BrdU) labeling on acquired resistance to subsequent nephrotoxic insult. Hepatocyte growth factor (HGF)/c-Met axis and other related factors of cell cycle were analyzed.
The acquired resistance to rechallenge injury with nephrotoxic dose of UA in rats recovered from mild renal injury was associated with an earlier increase in BrdU-positive PT cells, accelerated upregulation of HGF mRNA, c-Met mRNA/protein, cyclin D1, phospho-Rb and an earlier phenotypic change of PT cells. Colchicine inhibited PT cell proliferation, reduced the upregulated cyclin D1 and phospho-Rb in the kidney, completely abolishing acquired resistance.
Cell cycle progression with upregulated renal HGF/c-Met axis may contribute to the accelerated recovery from acute renal failure in rats that recovered from prior mild renal damage, followed by nephrotoxic insult, resulting in partial acquired resistance.
KeywordsAcquired resistance Acute renal failure Apoptosis Hepatocyte growth factor Proliferation Uranyl acetate
- 15.Korrapati MC, Chilakapati J, Lock EA, Latendresse JR, Warbritton A, Mehendale HM. Preplaced cell division: a critical mechanism of autoprotection against S-1, 2-dichlorovinyl-l-cysteine-induced acute renal failure and death in mice. Am J Physiol Renal Physiol. 2006;291:F439–55.PubMedCrossRefGoogle Scholar
- 23.Inoue H, Yokoyama F, Kita Y, Yoshiji H, Tsujimoto T, Deguchi A, et al. Relationship between the proliferative capability of hepatocytes and the intrahepatic expression of hepatocyte growth factor and c-Met in the course of cirrhosis development in rats. Int J Mol Med. 2006;17:857–64.PubMedGoogle Scholar
- 31.Witzgall R, Brown D, Schwarz C, Bonventre JV. Localization of proliferating cell nuclear antigen, vimentin, c-fos, and clusterin in the post-ischemic kidney. Evidence for a heterogeneous genetic response among nephron segments, and a large pool of mitotically active and dedifferentiated cells. J Clin Invest. 1994;93:2175–88.PubMedCrossRefGoogle Scholar