Knockdown of histone deacetylase 1 in fibroblasts and pericytes prevents renal interstitial fibrosis after ischemia-reperfusion injury.

Abstract

Ischemia-reperfusion injury (IRI), one form of acute kidney failure, often occurs after cardiovascular or renal surgery where there is a decline in blood flow through the kidney. This injury causes damage to renal cells and can lead to the formation of interstitial fibrosis, which will increase the risk of chronic kidney disease. The histone deacetylases (HDAC) protein family controls the expression of genes via epigenetic regulation of deacetylating histone lysine residues. We published that within an hour of bilateral IRI, in male mice, there was an increase of HDAC1 in the epithelium and interstitial cells. Moreover, inhibition of HDAC1 prior to IRI resulted in attenuated interstitial fibrosis. Myofibroblasts secrete collagen contributing significantly to wound healing as well as the development of interstitial fibrosis and these cells are predominantly differentiated fibroblasts and pericytes. We hypothesized that the knockdown of HDAC1 in fibroblasts and pericytes will attenuate interstitial fibrosis in the kidney after IRI. Male control (HDAC1fl/fl) and iFibroblastHDAC1KO (HDAC1fl/fl, Col1A2-CreER, hemizygous mice) were used in the experiment. The mice underwent bilateral renal artery and vein clamping for 18 minutes to induce IRI or sham surgery. Acute kidney injury was confirmed by serum creatinine measurements and determination of glomerular filtration rate (GFR) by transcutaneous FITC-sinistrin clearance 24 hours after injury. GFR was measured weekly for 4 weeks at which point the blood and kidneys were collected for analysis. Renal interstitial fibrosis was quantified by measuring the percentage coverage area of collagen stained by picrosirius red staining. 24 hours after surgery, IRI mice serum creatinine levels were greater in control mice 0.53 mg/dl ± 0.17, n = 9, and iFibHDAC1KO IRI mice 0.25 mg/dl ± 0.053, n = 10, compared to sham mice (control 0.084 mg/dl ± 0.008, n = 5, KO 0.098 mg/dl ± 0.006, n = 4, Pgenotype = 0.3, Psurgery = 0.028, Pinteraction = 0.25). This agreed with the measured GFR that was significantly reduced in the IRI mice (control IRI = 426 ul/min/100g ± 132, KO IRI = 529 ul/min/100g ± 116, Sham control = 1180 ul/min/100g ± 178, sham KO = 1188 ul/min/100g ± 156, Pgenotype = 0.71, Psurgery = 0.0003, Pinteraction = 0.75). The percentage of the collagen-positive area was significantly higher in control than in sham mice (p = 0.0011), while there was no noticeable difference (p = 0.9) between iFibHDAC1KO and sham mice (control IRI = 1.2 % ± 0.2, KO IRI = 0.47% ± 0.12, sham control = 0.35% ± 0.085, sham KO = 0.401% ± 0.073). In conclusion, HDAC1 is activated by IRI in the myofibroblast and promotes interstitial fibrosis. Funding resources: NIH NIDDK R01DK126664, UAB-UCSD O'Brien Center, and the Priya Nagar M.D. Foundation. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.