Biology subjects

Soler, M. J.

Publications and source records attributed to Soler, M. J..

3 recordsLinked to original sources

bioRxiv2021

Cell Sex and Sex Hormones Modulate Kidney Glucose and Glutamine Metabolism in Health and Diabetes

Male sex is a risk factor for progression of diabetic kidney disease, but the reasons for this predilection are unclear. Here, we demonstrate that cell sex and sex hormones alter the metabolic phenotype of human proximal tubular epithelial cells (PTECs). Male PTECs displayed increased glycolysis, mitochondrial respiration, oxidative stress, apoptosis, and high glucose-induced injury, compared to female PTECs. This phenotype was enhanced by dihydrotestosterone (DHT) and linked to increased mitochondrial utilization of glucose and glutamine. Studies in vivo pointed towards increased glutamine anaplerosis in diabetic male kidneys. Male sex was linked to increased levels of glutamate, TCA cycle, and glutathione cycle metabolites, in PTECs and in the blood metabolome of healthy youth and youth with type 2 diabetes. Conversely, female PTECs displayed increased levels of pyruvate, glutamyl-cysteine, cysteinylglycine, and a higher GSH/GSSG ratio than male PTECs, indicative of enhanced redox homeostasis. Finally, we identified transcriptional mechanisms that control kidney metabolism in a sex-specific fashion. While X-linked demethylase KDM6A facilitated metabolic homeostasis in female PTECs, transcription factor HNF4A mediated the deleterious effects of DHT in male PTECs. This work uncovers the role of sex in glucose/glutamine metabolism, that may explain the roots of sex dimorphism in the healthy and diabetic kidney.

cell biology↗

bioRxiv2021

Novel Human Lung Tissue Model for the Study of SARS-CoV-2 Entry, Inflammation and New Therapeutics

The development of physiological models that reproduce SARS-CoV-2 infection in primary human cells will be instrumental to identify host-pathogen interactions and potential therapeutics. Here, using cell suspensions directly from primary human lung tissues (HLT), we have developed a rapid platform for the identification of viral targets and the expression of viral entry factors, as well as for the screening of viral entry inhibitors and anti-inflammatory compounds. The direct use of HLT cells, without long-term cell culture and in vitro differentiation approaches, preserves main immune and structural cell populations, including the most susceptible cell targets for SARS-CoV-2; alveolar type II (AT-II) cells, while maintaining the expression of proteins involved in viral infection, such as ACE2, TMPRSS2, CD147 and AXL. Further, antiviral testing of 39 drug candidates reveals a highly reproducible method, suitable for different SARS-CoV-2 variants, and provides the identification of new compounds missed by conventional systems, such as VeroE6. Using this method, we also show that interferons do not modulate ACE2 expression, and that stimulation of local inflammatory responses can be modulated by different compounds with antiviral activity. Overall, we present a relevant and rapid method for the study of SARS-CoV-2. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/440731v2_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@96abf6org.highwire.dtl.DTLVardef@1f3cfe3org.highwire.dtl.DTLVardef@1d55fdborg.highwire.dtl.DTLVardef@1884cd6_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsEx vivo physiological systems for the study of SARS-CoV-2-host interactions are scarce. Here, we establish a method using primary human lung tissue (HLT) cells for the rapid analysis of cell tropism and identification of therapeutics. O_LIHLT cells preserve main cell subpopulations, including alveolar type-2 cells, and expression of SARS-CoV-2 entry factors ACE2, CD147, TMPRSS2 and AXL. C_LIO_LIHLT cells are readily susceptible to SARS-CoV-2 infection without the need of cell isolation or further cell differentiation. C_LIO_LIAntiviral testing in HLT cells allows the rapid identification of new drug candidates against SARS-CoV-2 variants, missed by conventional systems. C_LIO_LILocal inflammation is supported in HLT cells and offers the identification of relevant anti-inflammatory compounds for SARS-CoV-2 infection. C_LI

microbiology↗

bioRxiv2020

Kidney and Lung ACE2 expression after an ACE inhibitor or an Ang II receptor blocker: implications for COVID-19

BackgroundThere have been concerns that ACE inhibitors and Ang II receptor blockers may cause an increase in ACE2, the main receptor for SARs-CoV-2. MethodsKidneys from two genetic models of kidney ACE ablation and mice treated with captopril or telmisartan were used to examine ACE2 in isolated kidney and lung membranes. ResultsIn a global ACE KO mice, ACE2 protein abundance in kidney membranes was reduced to 42 % of wild type, p < 0.05. In ACE 8/8 mice that over-expresses cardiac ACE protein but also has no kidney ACE expression, ACE2 protein in kidney membranes was also decreased (38 % of the WT, p<0.01). In kidney membranes from mice that received captopril or telmisartan for 2 weeks there was a reduction in ACE2 protein (37% in captopril treated p<0.01) and 76% in telmisartan treated p <0.05). In lung membranes the expression of ACE2 was very low and not detected by western blotting but no significant differences in terms of ACE2 activity could be detected in mice treated with captopril (118% of control) or telmisartan (93% of control). ConclusionsGenetic kidney ACE protein deficiency, suppressed enzymatic activity by Captopril or blockade of the AT1 receptor with telmisartan are all associated with a decrease in ACE2 in kidney membranes. ACE2 protein in kidney or lungs is decreased or unaffected by RAS blockers indicating that these medications can not pose a risk for SARS-CoV-2 infection related to amplification of ACE2 at these two target sites for viral entry.

physiology↗