The regulation of VPS34 and WNK1 kinase in the proximal tubule of the kidney in health and disease

The proximal tubule (PT) is a high metabolic segment of the kidney. It possesses a reduced glycolytic activity and relies on oxidative mitochondrial metabolism to satisfy its energy demands. This peculiar characteristic makes the PT especially vulnerable to ischemic, hypoxic and metabolic injuries. The function of the PT after glomerular filtration is to reabsorb the number of solutes to avoid excessive loss of vital metabolites but dysfunctions of the proximal tubule can cause excessive excretion of glucose, amino acids and low-molecular weight proteins. The class III phosphoinositide 3-kinase VPS34 and the with-no-lysine [K] (WNK) kinases, have a wide range of functions and are both related to a disease context.The aim of this thesis was to analyze changes in the proximal tubule epithelial cell morphology, function and gene expression using two distinct animal models with conditional knockout of Vps34 and Vhl respectively in the proximal tubule

A Gemini–NIFS view of the merger remnant NGC 34

The merger remnant NGC 34 is a local luminous infrared galaxy (LIRG) hosting a nuclear starburst and a hard X-ray source associated with a putative, obscured Seyfert 2 nucleus. In this work, we use adaptive optics assisted near-infrared (NIR) integral field unit observations of this galaxy to map the distribution and kinematics of the ionized and molecular gas in its inner 1.2kpc×1.2kpc⁠, with a spatial resolution of 70 pc. The molecular and ionized gas kinematics is consistent with a disc with projected major axis along a mean PA = −9∘.2 ± 0∘.9. Our main findings are that NGC 34 hosts an AGN and that the nuclear starburst is distributed in a circumnuclear star formation ring with inner and outer radii of ≈ 60 and 180 pc, respectively, as revealed by maps of the [FeII]/Paβ and H2/Br γ emission-line ratios, and corroborated by PCA tomography analysis. The spatially resolved NIR diagnostic diagram of NGC 34 also identifies a circumnuclear structure dominated by processes related to the stellar radiation field and a nuclear region where [FeII] and H2 emissions are enhanced relative to the hydrogen recombination lines. We estimate that the nuclear X-ray source can account for the central H2 enhancement and conclude that [FeII] and H2 emissions are due to a combination of photoionization by young stars, excitation by X-rays produced by the AGN and shocks. These emission lines show nuclear, broad, blueshifted components that can be interpreted as nuclear outflows driven by the AGN

A Gemini–NIFS view of the merger remnant NGC 34

The merger remnant NGC 34 is a local luminous infrared galaxy (LIRG) hosting a nuclear starburst and a hard X-ray source associated with a putative, obscured Seyfert 2 nucleus. In this work, we use adaptive optics assisted near-infrared (NIR) integral field unit observations of this galaxy to map the distribution and kinematics of the ionized and molecular gas in its inner 1.2kpc×1.2kpc⁠, with a spatial resolution of 70 pc. The molecular and ionized gas kinematics is consistent with a disc with projected major axis along a mean PA = −9∘.2 ± 0∘.9. Our main findings are that NGC 34 hosts an AGN and that the nuclear starburst is distributed in a circumnuclear star formation ring with inner and outer radii of ≈ 60 and 180 pc, respectively, as revealed by maps of the [FeII]/Paβ and H2/Br γ emission-line ratios, and corroborated by PCA tomography analysis. The spatially resolved NIR diagnostic diagram of NGC 34 also identifies a circumnuclear structure dominated by processes related to the stellar radiation field and a nuclear region where [FeII] and H2 emissions are enhanced relative to the hydrogen recombination lines. We estimate that the nuclear X-ray source can account for the central H2 enhancement and conclude that [FeII] and H2 emissions are due to a combination of photoionization by young stars, excitation by X-rays produced by the AGN and shocks. These emission lines show nuclear, broad, blueshifted components that can be interpreted as nuclear outflows driven by the AGN

The AGNIFS survey : distribution and excitation of the hot molecular and ionized gas in the inner kpc of nearby AGN hosts

We use the Gemini NIFS instrument to map the H22.1218μm and Brγ flux distributions in the inner 0.04–2 kpc of a sample of 36 nearby active galaxies (0.001 ≲ z ≲ 0.056) at spatial resolutions from 4 to 250 pc. We find extended emission in 34 galaxies. In ∼55 per cent of them, the emission in both lines is most extended along the galaxy major axis, while in the other 45 per cent the extent follows a distinct orientation. The emission of H2 is less concentrated than that of Brγ, presenting a radius that contains half of the flux 60 per cent greater, on average. The H2 emission is driven by thermal processes – X-ray heating and shocks – at most locations for all galaxies, where 0.4 6 (seen in 40 per cent of the galaxies), shocks are the main H2 excitation mechanism, while in regions with H2/Brγ < 0.4 (25 per cent of the sample) the H2 emission is produced by fluorescence. The only difference we found between type 1 and type 2 active galactic nucleus (AGN) was in the nuclear emission-line equivalent widths that are smaller in type 1 than in type 2 due to a larger contribution to the continuum from the hot dusty torus in the former. The gas masses in the inner 125 pc radius are in the range 101−104 M⊙ for the hot H2 and 103−106 M⊙ for the ionized gas and would be enough to power the AGN in our sample for 105−108 yr at their current accretion rates

Cathepsin B increases ENaC activity leading to hypertension early in nephrotic syndrome

The NPHS2 gene, encoding the slit diaphragm protein podocin, accounts for genetic and sporadic forms of nephrotic syndrome (NS). Patients with NS often present symptoms of volume retention, such as oedema formation or hypertension. The primary dysregulation in sodium handling involves an inappropriate activation of the epithelial sodium channel, ENaC. Plasma proteases in a proteinuria‐dependent fashion have been made responsible; however, referring to the timeline of symptoms occurring and underlying mechanisms, contradictory results have been published. Characterizing the mouse model of podocyte inactivation of NPHS2 (Nphs2∆pod) with respect to volume handling and proteinuria revealed that sodium retention, hypertension and gross proteinuria appeared sequentially in a chronological order. Detailed analysis of Nphs2∆pod during early sodium retention, revealed increased expression of full‐length ENaC subunits and αENaC cleavage product with concomitant increase in ENaC activity as tested by amiloride application, and augmented collecting duct Na+/K+‐ATPase expression. Urinary proteolytic activity was increased and several proteases were identified by mass spectrometry including cathepsin B, which was found to process αENaC. Renal expression levels of precursor and active cathepsin B were increased and could be localized to glomeruli and intercalated cells. Inhibition of cathepsin B prevented hypertension. With the appearance of gross proteinuria, plasmin occurs in the urine and additional cleavage of γENaC is encountered. In conclusion, characterizing the volume handling of Nphs2∆pod revealed early sodium retention occurring independent to aberrantly filtered plasma proteases. As an underlying mechanism cathepsin B induced αENaC processing leading to augmented channel activity and hypertension was identified

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Peralkaline Felsic Magmatism of the Atlantic Islands

The oceanic-island magmatic systems of the Atlantic Ocean exhibit significant diversity in their respective sizes, ages, and the compositional ranges of their eruptive products. Nevertheless, almost all of the Atlantic islands and island groups have produced peralkaline felsic magmas, implying that similar petrogenetic regimes may be operating throughout the Atlantic Ocean, and arguably elsewhere. The origins of peralkaline magmas are frequently linked to low-degree partial melting of enriched mantle, followed by protracted differentiation in the shallow crust. However, additional petrogenetic processes such as magma mixing, crustal melting, and contamination have been identified at numerous peralkaline centers. The onset of peralkalinity leads to magma viscosities lower than those typical for metaluminous felsic magmas, which has profound implications for processes such as crystal settling. This study represents a compilation of published and original data which demonstrates trends that suggest that the peralkaline magmas of the Atlantic Ocean islands are generated primarily via extended (up to ∼ 95%), open system fractional crystallization of mantle-derived mafic magmas. Crustal assimilation is likely to become more significant as the system matures and fusible material accumulates in the crust. Magma mixing may occur between various compositional end-members and may be recognized via hybridized intermediate magmas. The peralkaline magmas are hydrous, and frequently zoned in composition, temperature, and/or water content. They are typically stored in shallow crustal magma reservoirs (∼ 2–5 km), maintained by mafic replenishment. Low melt viscosities (1 × 101.77 to 1 × 104.77 Pa s) facilitate two-phase flow, promoting the formation of alkali-feldspar crystal mush. This mush may then contribute melt to an overlying melt lens via filter pressing or partial melting. We utilize a three-stage model to account for the establishment, development, and termination of peralkaline magmatism in the ocean island magmatic systems of the Atlantic. We suggest that the overall control on peralkaline magmatism in the Atlantic is magma flux rate, which controls the stability of upper crustal magma reservoirs. The abundance of peralkaline magmas in the Atlantic suggests that their development must be a common, but not inevitable, stage in the evolution of ocean islands

Probing evolutionary population synthesis models in the near infrared with early-type galaxies

We performed a near-infrared (NIR; ∼1.0 –2.4 μm) stellar population study in a sample of early-type galaxies. The synthesis was performed using five different evolutionary population synthesis libraries of models. Our main results can be summarized as follows: low-spectral-resolution libraries are not able to produce reliable results when applied to the NIR alone, with each library finding a different dominant population. The two newest higher resolution models, on the other hand, perform considerably better, finding consistent results to each other and to literature values. We also found that optical results are consistent with each other even for lower resolution models. We also compared optical and NIR results and found out that lower resolution models tend to disagree in the optical and in the NIR, with higher fraction of young populations in the NIR and dust extinction ∼1 mag higher than optical values. For higher resolution models, optical and NIR results tend to agree much better, suggesting that a higher spectral resolution is fundamental to improve the quality of the results

Probing evolutionary population synthesis models in the near infrared with early-type galaxies

We performed a near-infrared (NIR; ∼1.0 –2.4 μm) stellar population study in a sample of early-type galaxies. The synthesis was performed using five different evolutionary population synthesis libraries of models. Our main results can be summarized as follows: low-spectral-resolution libraries are not able to produce reliable results when applied to the NIR alone, with each library finding a different dominant population. The two newest higher resolution models, on the other hand, perform considerably better, finding consistent results to each other and to literature values. We also found that optical results are consistent with each other even for lower resolution models. We also compared optical and NIR results and found out that lower resolution models tend to disagree in the optical and in the NIR, with higher fraction of young populations in the NIR and dust extinction ∼1 mag higher than optical values. For higher resolution models, optical and NIR results tend to agree much better, suggesting that a higher spectral resolution is fundamental to improve the quality of the results