Acquired resistance to rechallenge injury after acute kidney injury in rats is associated with cell cycle arrest in proximal tubule cells.

Abstract

Rats that have recovered from severe proximal tubule (PT) injury induced by uranyl acetate (UA), a toxic stimulus, developed resistance to subsequent UA treatment. We investigated cell cycle status and progression in PT cells in relation to this acquired resistance. Fourteen days after pretreatment with saline (vehicle group) or UA [acute kidney injury (AKI) group], rats were injected with UA or lead acetate (a proliferative stimulus). Cell cycle status (G0/G1/S/G2/M) was analyzed by flow cytometry. The expression of cell cycle markers, cyclin-dependent kinase inhibitors, and phenotypic markers were examined by immunohistochemistry. Cell cycle status in PT cells in the AKI group was comparable to those of the vehicle group. However, more early G1-phase cells (cyclin D1- or Ki67-) and p21+ or p27+ cells were found in the PT of the AKI group than in that of the vehicle group. UA induced G1 arrest and inhibited S phase progression with earlier dedifferentiation and less apoptosis in PT cells of the AKI group. Lead acetate induced proliferation without dedifferentiation but with delayed G0-G1 transition and inhibited S phase progression in PT cells in the AKI group. Sustained p21 and increased p27 expression in PT cells were found in the AKI group in response to UA and lead acetate. PT cells in the AKI group inhibited cell cycle progression by enhanced G1 arrest, probably via p21/p27 modulation as an injury or proliferation response, resulting in cytoresistance to rechallenge injury.

• Authors: Takamasa Iwakura, Yoshihide Fujigaki, Tomoyuki Fujikura, Naro Ohashi, Akihiko Kato, Hideo Yasuda
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 310 Issue 9 Pg. F872-84 (05 01 2016) ISSN: 1522-1466 [Electronic] United States
• PMID: 26823281 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 the American Physiological Society.

Chemical References

• Cell Cycle Proteins
• Organometallic Compounds
• uranyl acetate
• p21-Activated Kinases
• Cyclin-Dependent Kinases
• lead acetate

Topics

• Acute Kidney Injury (chemically induced, pathology)
• Animals
• Apoptosis (drug effects)
• Cell Cycle Checkpoints
• Cell Cycle Proteins (biosynthesis)
• Cell Dedifferentiation (drug effects)
• Cyclin-Dependent Kinases (biosynthesis)
• Kidney Tubules, Distal (cytology, drug effects)
• Kidney Tubules, Proximal (pathology)
• Male
• Organometallic Compounds
• Rats
• Rats, Sprague-Dawley
• Recurrence
• p21-Activated Kinases (biosynthesis)