Biology subjects

Hinds, T. D.

Publications and source records attributed to Hinds, T. D..

4 recordsLinked to original sources

bioRxiv2024

Renal-Derived Human sPRR Does Not Increase Blood Pressure in High Fat Diet Mice

Obesity is a risk factor for hypertension. Obesity-related hypertension has been associated with elevated plasma soluble prorenin receptor (sPRR) particularly in men. Additionally, renal PRR and sPRR protein expression is upregulated during obesity and diabetes. However, whether renal-derived human sPRR (HsPRR) may influence the intrarenal RAS status to regulate blood pressure and kidney function during obesity has not been investigated. Therefore, we studied the role of collecting duct (CD) derived-HsPRR on blood pressure and kidney function in male and female mice during obesity. Eight-week-old male and female CD-HsPRR mice were placed on a high fat diet for 25 weeks. HsPRR increased renal sPRR concentration but did not change its circulating levels in male and female littermates compared to CTL mice. GFR, water intake and urine flow were not influenced by the CD-HsPRR expression in either sex. Moreover, after 21 weeks of HFD, blood pressure was similar between groups, while only male CD-HsPRR mice showed an impaired pressor response to losartan. In the renal cortex, male CD-HsPRR mice showed increased renin and AT1R mRNA expression associated with increased AQP2, and ENaC subunits protein expression. These data indicate that renal-derived HsPRR induces local upregulation in renin, AT1R and sodium/water transporters in male mice without altering renal hemodynamics or blood pressure. In obese females, CD-HsPRR expression did not affect blood pressure or renal function, which suggests that females may be protected from obesity induced renal function impairment and hypertension.

physiology↗

bioRxiv2023

Loss of Carnitine Palmitoyltransferase 1a Reduces Docosahexaenoic Acid-Containing Phospholipids and Drives Sexually Dimorphic Liver Disease in Mice

Background and AimsGenome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the impact by which liver-specific CPT1a deletion impacts hepatic lipid metabolism. Approach and ResultsSix-to-eight-week old male and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (HFD; 60% kcal fat) for 15 weeks. Mice were necropsied after a 16 hour fast, and tissues were collected for lipidomics, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), kinome analysis, RNA-sequencing, and protein expression by immunoblotting. Female LKO mice had increased serum alanine aminotransferase (ALT) levels which were associated with greater deposition of hepatic lipids, while male mice were not affected by CPT1a deletion relative to male control mice. Mice with CPT1a deletion had reductions in DHA-containing phospholipids at the expense of monounsaturated fatty acids (MUFA)-containing phospholipids in both whole liver and at the level of the lipid droplet (LD). Male and female LKO mice increased RNA levels of genes involved in LD lipolysis (Plin2, Cidec, G0S2) and in polyunsaturated fatty acid (PUFA) metabolism (Elovl5, Fads1, Elovl2), while only female LKO mice increased genes involved in inflammation (Ly6d, Mmp12, Cxcl2). Kinase profiling showed decreased protein kinase A (PKA) activity, which coincided with increased PLIN2, PLIN5, and G0S2 protein levels and decreased triglyceride hydrolysis in LKO mice. ConclusionsLiver-specific deletion of CPT1a promotes sexually dimorphic steatotic liver disease (SLD) in mice, and here we have identified new mechanisms by which females are protected from HFD-induced liver injury. Graphical Summary O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/553705v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@f42ea0org.highwire.dtl.DTLVardef@12135f2org.highwire.dtl.DTLVardef@15cd9d0org.highwire.dtl.DTLVardef@e0106b_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2023

GalNAc-siRNA Mediated Knockdown of Ketohexokinase Versus Systemic, Small Molecule Inhibition of its Kinase Activity Exert Divergent Effects on Hepatic Metabolism in Mice on a HFD

Consumption of diets high in sugar and fat are well-established risk factors for the development of obesity and its metabolic complications, including non-alcoholic fatty liver disease. Metabolic dysfunction associated with sugar intake is dependent on fructose metabolism via ketohexokinase (KHK). Here, we compared the effects of systemic, small molecule inhibition of KHK enzymatic activity to hepatocyte-specific, GalNAc-siRNA mediated knockdown of KHK in mice on a HFD. Both modalities led to an improvement in liver steatosis, however, via substantially different mechanisms. KHK knockdown profoundly decreased lipogenesis, while the inhibitor increased the fatty acid oxidation pathway. Moreover, hepatocyte-specific KHK knockdown completely prevented hepatic fructose metabolism and improved glucose tolerance. Conversely, KHK inhibitor only partially reduced fructose metabolism, but it also decreased downstream triokinase. This led to the accumulation of fructose-1 phosphate, resulting in glycogen accumulation, hepatomegaly, and impaired glucose tolerance. In summary, KHK profoundly impacts hepatic metabolism, likely via both kinase-dependent and independent mechanisms. HIGHLIGHTSO_LIKHK knockdown or inhibition of its kinase activity differently target hepatic metabolism. C_LIO_LIKHK inhibitor increases F1P and glycogen accumulation as it also lowers triokinase. C_LIO_LIKHK knockdown completely prevents hepatic fructose metabolism and lipogenesis. C_LIO_LIE of wild type, but not mutant, kinase dead KHK-C increases glycogen accumulation. C_LI

molecular biology↗

bioRxiv2022

Zinc Fingers and Homeoboxes 2 is Required for Diethylnitrosamine-induced Liver Tumor Formation in C57BL/6 Mice

Liver cancer, comprised mainly of hepatocellular carcinoma (HCC), is the third leading cause of cancer deaths worldwide and increasing in Western countries. We previously identified the transcription factor Zinc Fingers and Homeoboxes 2 (Zhx2) as a regulator of hepatic gene expression, and many Zhx2 target genes are dysregulated in HCC. Here, we investigate HCC in Zhx2-deficient mice using the Diethylnitrosamine (DEN)-induced liver tumor model. Our study using whole-body Zhx2 knock-out (Zhx2KO) mice revealed the complete absence of liver tumors 9 and 10 months after DEN exposure.Analysis soon after DEN treatment showed no differences in expression of the DEN bioactivating enzyme CYP2E1 and DNA polymerase delta 2, or in the numbers of {gamma}H2AX foci between Zhx2KO and wild-type (Zhx2wt) mice. The absence of Zhx2, therefore, did not alter DEN bioactivation or DNA damage. Zhx2KO livers showed fewer positive foci for Ki67 staining and reduced IL-6 and AKT2 expression compared to Zhx2wt livers, suggesting that Zhx2 loss reduces liver cell proliferation and may account for reduced tumor formation. Tumors were reduced but not absent in DEN-treated liver-specific Zhx2 knock-out mice, suggesting that Zhx2 acts in both hepatocytes and non-parenchymal cells to inhibit tumor formation. Analysis of data from The Cancer Genome Atlas and Clinical Proteomic Tumor Consortium indicated that ZHX2 mRNA and protein levels were significantly higher in HCC patients and associated with clinical pathological parameters. ConclusionsIn contrast to previous studies in human hepatoma cell lines and other HCC mouse models showing that Zhx2 acts as a tumor suppressor, our data indicate that Zhx2 acts as an oncogene in the DEN-induced HCC model and is consistent with the higher ZHX2 expression in HCC patients.

cancer biology↗