Klf9 plays a critical role in GR -dependent metabolic adaptations in cardiomyocytes.

Glucocorticoids through activation of the Glucocorticoid receptor (GR) play an essential role in cellular homeostasis during physiological variations and in response to stress. Our genomic GR binding and transcriptome data from Dexamethasone (Dex) treated cardiomyocytes showed an early differential regulation of mostly transcription factors, followed by sequential change in genes involved in downstream functional pathways. We examined the role of Krüppel-like factor 9 (Klf9), an early direct target of GR in cardiomyocytes. Klf9-ChIPseq identified 2150 genes that showed an increase in Klf9 binding in response to Dex. Transcriptome analysis of Dex treated cardiomyocytes with or without knockdown of Klf9 revealed differential regulation of 1777 genes, of which a reversal in expression is seen in 1640 genes with knockdown of Klf9 compared to Dex. Conversely, only 137 (∼8%) genes show further dysregulation in expression with siKLf9, as seen with Dex treated cardiomyocytes. Functional annotation identified genes of metabolic pathways on the top of differentially expressed genes, including those involved in glycolysis and oxidative phosphorylation. Knockdown of Klf9 in cardiomyocytes inhibited Dex induced increase in glycolytic function and mitochondrial spare respiratory capacity, as measured by glycolysis and mito stress tests, respectively. Thus, we conclude that cyclic, diurnal GR activation, through Klf9 -dependent feedforward signaling plays a central role in maintaining cellular homeostasis through metabolic adaptations in cardiomyocytes.

Carbon tetrachloride-induced nephrotoxicity in rats: protective role of Digera muricata.

Digera muricata is used in renal disorders in folk medicine. Generation of reactive radicals has been implicated in carbon tetrachloride-induced nephrotoxicity, which are involved in lipid peroxidation, accumulation of dysfunctional proteins, leading to injuries in kidneys. The present study was aimed to evaluate the efficacy of Digera muricata on the kidney function in CCl(4)-induced injuries. CCl(4) treatment (5 ml/kg body wt., i.p. CCl(4):olive oil; 1:9) significantly increased the level of urine creatinine, protein, nitrite, urobilinogen, red blood cells (RBCs), leucocytes count, and levels of blood urea nitrogen (BUN). Level of proteins and DNA fragmentation %, argyrophilic nucleolar organizer regions (AgNORs) count in renal tissues was also significantly increased. Activity of antioxidant enzymes; catalase, peroxidase, superoxide dismutase and reduced glutathione (GSH) were decreased while thiobarbituric acid reactive substances (TBARSs) were increased with CCl(4) treatment. DNA ladder assay was intimately related with the DNA fragmentation assay. Telomerase activity was determined in the CCl(4)-treated renal tissue homogenate. Treatment with n-hexane (HDMP) and methanolic (MDMP) extracts of Digera muricata (200 and 250 mg/kg body wt., oral, respectively) effectively attenuated the alterations in the biochemical markers, telomerase activity was inhibited and confirms the restoration of normalcy and accredits the protective role of Digera muricata against CCl(4)-induced nephrotoxicity.