Biology subjects

Arthur, G.

Publications and source records attributed to Arthur, G..

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↗

bioRxiv2024

Human Soluble Prorenin Receptor Expressed in Adipose Tissue Improves Insulin Sensitivity and Endothelial Function in Obese Female Mice

Soluble prorenin receptor (sPRR) is a component of the renin-angiotensin system (RAS) identified as a plasma biomarker for human metabolic disease. However, what tissue source of sPRR is implicated in the modulation of metabolic function remains unclear. This study investigated the contribution of human sPRR (HsPRR) produced in the adipose tissue (Adi) on the metabolic and cardiovascular function of lean and obese male and female mice. Adi-HsPRR mice, generated by crossing human sPRR-Myc-tag and Adiponectin/Cre mice, were fed a low-fat or high-fat diet (10% and 60% kCal from fat, respectively) for 20 weeks. Obese Adi-HsPRR mice showed elevated sPRR levels in adipose tissue without affecting adipocyte size or fat depot weight. Despite plasma sPRR being similar between obese Adi-HsPRR and control female mice, a positive correlation between plasma sPRR and adiposity was present only in controls. Obese Adi-HsPRR male mice showed elevated plasma sPRR compared with controls, but no correlation with adiposity was found in either group. Nevertheless, Adi-HsPRR expression improved insulin sensitivity and endothelial function, reduced adipogenic genes mRNA abundance (PPARg, SEBP1C and CD36), and increased plasma Angiotensin 1-7 levels only in obese HsPPR female mice. Taken together, elevated HsPRR in adipose tissue improved metabolic and vascular function in obese female mice despite normal circulating levels of sPRR, whereas increased local and circulating levels of HsPRR did not influence metabolic and cardiovascular function in obese male mice. Our data suggest that increased plasma sPRR associated with metabolic disease could be produced by other tissues rather than adipocytes.

physiology↗

bioRxiv2020

ATM-deficient lung, prostate and pancreatic cancer cells are acutely sensitive to the combination of olaparib and the ATR inhibitor AZD6738

BackgroundThe ataxia telangiectasia mutated (ATM) protein kinase is mutated in several human cancers, presenting potential opportunities for targeted cancer therapy. We previously reported that the poly-ADP ribose polymerase (PARP) inhibitor olaparib induced transient G2 arrest but not cell death in ATM-deficient A549 lung cancer cells, while the combination of olaparib with the ATM-, Rad3-related (ATR) inhibitor VE-821 induced cell death. Here, we show that the clinically relevant ATR inhibitor, AZD6738, sensitizes ATM-deficient A549 lung, prostate and pancreatic cancer cells to olaparib. MethodsATM was depleted from A549 lung cancer cells, PC-3 prostate cancer cells and Panc 10.05 pancreatic cancer cells, and the effects of olaparib alone and in combination with AZD6738 were determined. ResultsThe combination of olaparib plus AZD6738 induced cell death in ATM-deficient lung, prostate and pancreatic cancer cells with little effect on their ATM-proficient counterparts. ConclusionsLung, prostate and pancreatic patients whose tumours exhibit loss or inactivation of ATM may benefit from combination of a PARP inhibitor plus an ATR inhibitor.

cancer biology↗

bioRxiv2020

The Prorenin Receptor and its Soluble Form Contribute to Lipid Homeostasis

Obesity is associated with alterations in hepatic lipid metabolism. We previously identified the prorenin receptor (PRR) as a potential contributor to liver steatosis. Therefore, we aimed to determine the relative contribution of PRR and its soluble form, sPRR, to lipid homeostasis. PRR-floxed male mice were treated with an adeno-associated virus with thyroxine-binding globulin promoter driven Cre to delete specifically PRR in hepatocytes (Liver PRR KO mice). Hepatic PRR deletion did not change the body weight but increased liver weights. Liver PRR KO mice exhibited higher plasma cholesterol levels and lower hepatic LDLR protein than control mice. Surprisingly, hepatic PRR deletion elevated hepatic cholesterol, and up-regulated hepatic SREBP2 and HMG CoA-R genes. In addition, hepatic PRR deletion increased plasma sPRR levels. In vitro studies in Hep-G2 cells demonstrated that sPRR treatment up-regulated SREBP2 suggesting that elevated plasma sPRR could contribute to hepatic cholesterol biosynthesis. Interestingly, PPAR{gamma}, PRR and total sPRR were elevated in the adipose tissue of Liver PRR KO mice suggesting that elevated plasma sPRR originated from the adipose tissue. In 3T3-L1 cells, sPRR treatment up-regulated PPAR{gamma} indicating that sPRR stimulates master regulator of adipocyte differentiation. Overall, this work support a new role for sPRR in lipid metabolism and adipose tissue - liver crosstalk.

physiology↗