Essential Roles of the Histone Demethylase KDM4C in Renal Development and Acute Kidney Injury

Abstract

Background: Lysine demethylase 4C (KDM4C) is a nuclear protein that is essential for histone modification and acts as an important regulator of several transcription factors. Previous studies have shown that KDM4C may also play a role in mediating stress responses. The purpose of this study was to examine the roles of KDM4C in kidney development and acute kidney injury (AKI). Methods: The effect of KDM4C on kidney development was assessed by comparing the kidney phenotype between 96 zebrafish embryos treated with kdm4c-morpholino oligonucleotide and 96 untreated zebrafish embryos. We further examined whether KDM4C is essential for maintaining cell survival in AKI. Cultured human renal tubular cells were used for the in vitro study. Wild-type and Kdm4c knockout mice (C57BL/6NTac-Kdm4ctm1a(KOMP)Wtsi) were divided into a sham group and model group, and then subjected to ischemic reperfusion kidney injury (IRI-AKI). Blood samples and kidneys were collected at different time points (day 3, day 7, day 14, and day 28) and were processed for in vivo studies (n = 8 in each group). Results: Kdm4c knockdown significantly decreased zebrafish embryo survival and impaired kidney development. The in vitro study showed that KDM4C inhibition by JIB04 significantly increased cellular apoptosis under oxidative stress conditions. KDM4C knockdown cells had impaired autophagy function under stress conditions. The IRI-AKI mice study showed that KDM4C protein levels dynamically changed and were significantly correlated with HIF-1α levels in AKI. Kdm4c−/− mice had significantly more severe renal impairment and increased kidney fibrosis than the wild-type mice. Cytokine array results also indicated that the kidneys of Kdm4c−/− mice had increased inflammation in AKI compared with the wild-type mice. Further RNA sequence analysis revealed that KDM4C may regulate transcription factors related to mitochondrial dynamics and function. Conclusions: Our study suggests that KDM4C may play a critical role in regulating mitochondria, which is related to a protective effect on maintaining cell survival in AKI.

Identification of single nucleotide polymorphisms (SNPs) associated with chronic graft-versus-host disease in patients undergoing allogeneic hematopoietic cell transplantation

“…Furthermore, KDM4 demethylases have been determined as integral for long term-maintenance of hematopoiesis using mouse models [ 53 ]. It has been suggested that KDM4C is essential to the survival of cells under stress and plays a role in kidney development by regulating autophagy [ 54 ]. Although it is rare, cases of cGVHD of the kidneys have been reported in approximately 1% of patients undergoing allogeneic HCT and the risk of chronic kidney disease is increased in long-term survivors [ 55 , 56 ].…”

Histone demethylases in the regulation of immunity and inflammation

“…There was growing evidence that abnormal expression of KDMs was associated with a variety of inflammatory diseases, including mastitis, liver fibrosis, inflammatory kidney injury, inflammatory pulmonary injury, colitis, autoimmune diseases, and inflammationrelated cancers [96,[142][143][144]. The expression of KDMs was upregulated or down-regulated in these diseases, and the transcription and secretion of inflammatory mediators were regulated through specific demethylation or activation of inflammation-related pathways, thus promoting the occurrence and development of inflammatory diseases [133,[145][146][147][148] (Table 1). Since there are so many inflammatory diseases that may involve the dysfunction of KDMs, this review we discuss six of the following inflammatory diseases.…”

Epigenetic regulation of mitochondrial‐endoplasmic reticulum dynamics in kidney diseases

“…Lysine demethylase 4C (KDM4C) is a nuclear protein demethylase Lys‐9 and Lys‐36 residues of histone H3 (Kupershmit et al, 2014). Recently it was observed that KDM4C is an essential gene for kidney development and regulates several transcription factors that drive mitochondrial dynamics and function in the kidney (Pan et al, 2022). During AKI, increased KDM4C regulates and increases the expression of autophagic transcription factors such as LC3B II, LC3, BCL2, beclin‐1, and ATG5.…”

“…Moreover, KDM4C controls mitochondrial function by regulating mitochondrial electron transport chain. The KDM4C knockdown alters the mitochondrial electron transport chain and oxidative phosphorylation and decreases autophagic transcription factors during AKI (Pan et al, 2022). However, this study lacks more confirmation about this link, therefore, still more understanding is needed in this context.…”