Stathmin-deficient mice develop fibrosis and show delayed recovery from ischemic-reperfusion injury

Abstract

In kidneys subjected to ischemic reperfusion injury (IRI) stathmin, a tubulin-binding protein involved in the regulation of mitosis, is expressed in dedifferentiated and proliferating renal tubule cells during the recovery phase. To ascertain the role of stathmin in the recovery from ischemic kidney injury, stathmin-deficient (OP18-/-) and wild-type (WT) animals were subjected to experimental IRI. At 3, 7, and 14 days after reperfusion serum samples and kidneys were collected for the examination of parameters of renal function, morphology, and recovery. Our studies indicate that on day 14 after reperfusion OP18-/- mice have significant renal failure, whereas the creatinine levels of WT animals have returned to baseline. Compared with WT animals OP18-/- mice had more extensive tubular fibrosis. The examination of proliferating cell nuclear antigen expression indicated that OP18-/- animals have increased proliferative or DNA repair activity for a more prolonged duration. The OP18-/- animals also had an increased number of tubules with apoptotic cells. These results suggest that in stathmin-deficient mice subjected to IRI, the aberrant regulation of cell cycle progression, not observed under normal conditions, impairs or at least delays the process of tubular repair and recovery after acute renal injury.

Histone Deacetylase Inhibitor Enhances Recovery after AKI

“…41 Additionally, renal tubular repair activates inflammatory programs that drive interstitial fibrosis, 42 and G2/M arrest of surviving RTECs is a maladaptive repair mechanism that delays recovery and promotes postinjury fibrosis in models of severe AKI. 14,15,31 Because we have shown that m4PTB decreases the proportion of surviving RTECs in G2/M phase after IR-AKI, these data suggest that m4PTB may decrease postinjury fibrosis by driving RTECs through the G2/M checkpoint, promoting repopulation of the injured tubule with healthy, differentiated RTECs.…”

“…There was also no change in the proportion of PCNA-positive tubular epithelial cells of the total number of actively cycling (Ki67-positive) tubular epithelial cells ( Figure 7C). Because kidney injury induces G2/M arrest in surviving RTECs, 15,31 we evaluated the proportion of proliferating (Ki67-positive) cells in the G2 and M phases of the cell cycle in m4PTB-treated kidneys 72 hours after injury. Phosphorylated Ser 10 histone H3 (pH3) is expressed at high levels in late G2-and M-phase cells.…”

KIM-1–mediated phagocytosis reduces acute injury to the kidney

“…Renal function and histology Plasma creatinine was determined by the picric acid method (49). Kidney histology was examined in formalin-fixed, H&E-stained sections.…”

Comparison of protective effects of trimetazidine against experimental warm ischemia of different durations: early and long-term effects in a pig kidney model

“…A and B: expression of stathmin and HIF-1␣, respectively, was examined by Western blotting in cortex and outer medulla at days 0, 3, and 7 after reperfusion. C: representative immunoblots for stathmin, HIF-1␣, and control actin after various durations of ischemia (45,60, and 90 min) followed by reperfusion and stathmin and HIF-1␣ expression in normal kidney (control) and uninephrectomized animals. Induction of stathmin and HIF-1␣ was observed at 72 h of reperfusion, particularly in the outer medulla in TMZ-treated groups, and this induction was delayed in no TMZ-treated groups.…”

“…In ATN, recent reports have shown that stathmin is a marker of dedifferentiated, mitotically active epithelial cells that may contribute to tubular regeneration after ATN (44). Interestingly, in stathmin-deficient mice subjected to IRI, aberrant regulation of cell cycle progression, which impaired or at least delayed the process of tubular repair and recovery after acute renal injury, has been described (45). The other relevant aspect, the role of the inflammatory process in damaged kidneys, has been studied in in vitro and in vivo models, which have evidenced that inflammation plays a major role in the pathophysiology of ARF resulting from ischemia.…”