Class-Specific Histone/Protein Deacetylase Inhibition Protects Against Renal Ischemia Reperfusion Injury and Fibrosis Formation

Abstract

Renal ischemia-reperfusion injury (IRI) is a common cause of renal dysfunction and renal failure. Histone/protein deacetylases (HDACs) regulate gene accessibility and higher order protein structures and may alter cellular responses to a variety of stresses. We investigated whether use of pan- and class-specific HDAC inhibitors (HDACi) could improve IRI tolerance in the kidney. Using a model of unilateral renal IRI, we investigated early renal function after IRI, and calculated fibrosis after IRI using an automated scoring system. We found that pan-HDAC inhibition using trichostatin (TSA) yielded significant renal functional benefit at 24–96 hours (p < 0.001). Treated mice developed significantly less fibrosis at 30 days (p < 0.0004). Class I HDAC inhibition with MS-275 yielded similar effects. Protection from fibrosis formation was also noted in a cold ischemia transplant model (p < 0.008) with a trend toward improved cold ischemic survival in TSA-treated mice. These effects were not accompanied by induction of typical ischemic tolerance pathways or by priming of heat shock protein expression. In fact, heat shock protein 70 deletion or overexpression did not alter renal ischemia tolerance. Micro-RNA 21, known to be enhanced in vitro in renal tubular cells that survive stress, was enhanced by treatment with HDACi, pointing to possible mechanism.

Improved renal ischemia tolerance in females influences kidney transplantation outcomes

“…Renal function was assessed daily for 4 days after IRI and was wholly attributable to the injured kidney. After a 28-day recovery period, mice were sacrificed and the degree of renal fibrosis quantitated using a computerized Sirius red scoring system (26). In this model, female C57BL/6 mice tolerated 28 minutes of warm IRI, with substantial but survivable injury that resulted in significant fibrosis (n = 10, Figure 1A).…”

“…Animals were s.c. injected with 100 ml/kg warm saline after the operation to assist in the maintenance of hydration. Animals were kept in an incubator (37°C) from the time of anesthetic administration until completely awake (26).…”

“…The native kidneys were left in situ for 5 days and removed under inhalational isoflurane anesthetic. Warm IRI experiments in the transplanted kidney were performed as outlined above, with microvascular clamping of the transplanted renal pedicle (26).…”

Targeting Sirtuin-1 prolongs murine renal allograft survival and function

“…Sirius Red-stained sections were scanned using the Aperio ScanScope1 CS slide scanner and analyzed using Aperio ImageScope software version 10.0.1346.1807 (Aperio Technologies, Vista, CA), as previously reported. 39 Subcapsular areas were excluded to limit the analysis to parenchymal changes. Features of tubular injury to include the presence of acute epithelial damage, protein casts, luminal inflammatory cells, tubular atrophy and regeneration; and interstitial changes including interstitial cellularity and inflammation were graded on a scale from 0–3.…”

A Class 1 Histone Deacetylase with Potential as an Antifungal Target

“…Hence, several natural and synthetic inhibitors of classical HDACs are already in use or are under evaluation in clinical trials against different types of cancer (16, 17). Several of these inhibitors show only little effect on normal tissues, and some of them are even specific for distinct HDAC classes (18, 19). …”