(Pro)renin receptor and V-ATPase: from Drosophila to humans

A decade ago, the (P)RR [(pro)renin receptor] was discovered and depicted as a potential activator of the tissue renin-angiotensin system. For this reason, the role of the (P)RR in cardiovascular diseases and diabetes has been particularly studied. However, the discovery of embryonic lethality after (P)RR gene deletion in mouse and zebrafish paved the way for additional roles of (P)RR in cell homoeostasis. Indeed, the (P)RR has been shown to associate with vacuolar H+-ATPase, hence its other name ATP6ap2. Developmental studies in Xenopus and Drosophila have revealed an essential role of this association to promote the canonical and non-canonical Wnt signalling pathways, whereas studies with tissue-specific gene deletion have pointed out a role in autophagy. The present review aims to summarize recent findings on the cellular functions of (P)RR emerging from various mutated and transgenic animal models

CXCL5 limits macrophage foam cell formation in atherosclerosis

The ELR+-CXCL chemokines have been described typically as potent chemoattractants and activators of neutrophils during the acute phase of inflammation. Their role in atherosclerosis, a chronic inflammatory vascular disease, has been largely unexplored. Using a mouse model of atherosclerosis, we found that CXCL5 expression was upregulated during disease progression, both locally and systemically, but was not associated with neutrophil infiltration. Unexpectedly, inhibition of CXCL5 was not beneficial but rather induced a significant macrophage foam cell accumulation in murine atherosclerotic plaques. Additionally, we demonstrated that CXCL5 modulated macrophage activation, increased expression of the cholesterol efflux regulatory protein ABCA1, and enhanced cholesterol efflux activity in macrophages. These findings reveal a protective role for CXCL5, in the context of atherosclerosis, centered on the regulation of macrophage foam cell formation

The (pro)renin receptor (ATP6ap2) facilitates receptor-mediated endocytosis and lysosomal function in the renal proximal tubule

The ATP6ap2 (Pro)renin receptor protein associates with H(+)-ATPases which regulate organellar, cellular, and systemic acid-base homeostasis. In the kidney, ATP6ap2 colocalizes with H(+)-ATPases in various cell types including the cells of the proximal tubule. There, H(+)-ATPases are involved in receptor-mediated endocytosis of low molecular weight proteins via the megalin/cubilin receptors. To study ATP6ap2 function in the proximal tubule, we used an inducible shRNA Atp6ap2 knockdown rat model (Kd) and an inducible kidney-specific Atp6ap2 knockout mouse model. Both animal lines showed higher proteinuria with elevated albumin, vitamin D binding protein, and procathepsin B in urine. Endocytosis of an injected fluid-phase marker (FITC- dextran, 10 kDa) was normal whereas processing of recombinant transferrin, a marker for receptor-mediated endocytosis, to lysosomes was delayed. While megalin and cubilin expression was unchanged, abundance of several subunits of the H(+)-ATPase involved in receptor-mediated endocytosis was reduced. Lysosomal integrity and H(+)-ATPase function are associated with mTOR signaling. In ATP6ap2, KO mice mTOR and phospho-mTOR appeared normal but increased abundance of the LC3-B subunit of the autophagosome was observed suggesting a more generalized impairment of lysosomal function in the absence of ATP6ap2. Hence, our data suggests a role for ATP6ap2 for proximal tubule function in the kidney with a defect in receptor-mediated endocytosis in mice and rats

Kpna6 deficiency causes infertility in male mice by disrupting spermatogenesis

Spermatogenesis is driven by an ordered series of events, which rely on trafficking of specific proteins between nucleus and cytoplasm. The importin α family of proteins mediates movement of specific cargo proteins when bound to importin β. Importin α genes have distinct expression patterns in mouse testis, implying they may have unique roles during mammalian spermatogenesis. Here we use a loss-of-function approach to specifically determine the role of importin α7 in spermatogenesis and male fertility. We show that ablation of importin α7 in male mice leads to infertility and has multiple cumulative effects on both germ cells and Sertoli cells. Importin α7-deficient mice exhibit an impaired Sertoli cell function, including loss of Sertoli cells and a compromised nuclear localization of the androgen receptor. Furthermore, our data demonstrate devastating defects in spermiogenesis including incomplete sperm maturation and massive loss of sperms that are accompanied by disturbed histone-protamine-exchange, differential localization of the transcriptional regulator Brwd1 and altered expression of Rfx2 target genes. Our work uncovers the essential role of importin α7 in spermatogenesis and hence in male fertility

Unprecedented light induced aggregation of cationic 1,4,5,8-naphthalenediimide amphiphiles

Bola amphiphiles from naphthalenediimide (NDI-bas) with quaternary ammonium groups (DC4, DaP, and DaO) display association in solution, as well as, surprisingly, visible light promoted photochromism in concentrated solutions of water, acetonitrile and THF. The photochromism is correlated with an aggregation process that leads to a significant modification of the electronic transitions, resulting in an unusual absorption band distribution that points out to a type of H-aggregation in transverse. This assembly can be reversibly broken up by heating at 70 °C and adding bulk salt (NaBF4). By 1H-NMR spectroscopic analysis of the irradiation/heating cycle the assembly/disassembly process can be followed by the changes in peak width and intensity. These photoinduced aggregates can sensitize dissolved O2 to give singlet oxygen, a surprising observation when it comes to sensitization efficiency for dyes where aggregation usually decreases the sensitization yield. Laser-induced luminescence measurements corroborate the existence of triplet states as phosphorescence was detected, being particularly intense in concentrated THF solutions

A Practical Approach of Teaching Digitalization and Safety Strategies in Cyber-Physical Production Systems

Digitalization strategies in cyber-physical production systems (CPPS) are one of the key factors of Industry 4.0. The topic not only addresses data preparation, real-time data processing, big data analytics, visualization and machine interface design but also cyber security and safety. Especially, unauthorized access to protected (personal or enterprise) data or unauthorized control of production facilities imply risks when it comes to digitalization. Because of the increased complexity of state-of-the-art technologies, educational institutions need to provide practice-oriented teaching methods in learning factories to help engineers of today understand the impact of those developments. In the light of this fact, this paper presents a practical approach of teaching digitalization strategies in CPPS. Planning, implementing and impacts of digitalization strategies are taught on a use-case with human-robot-collaboration. The objective of the use-case is to realize a real-time obstacle avoidance approach for a collaborative application based on a local positioning system. Here, students not only learn how to model the kinematics of a robot and program a robot but also how to design machine interfaces for real-time data transfer and processing as well as impacts of digitalization on safety and security. The implementation of the use-case is part of the TU Wien teaching portfolio and thus part of its learning factory, where students and apprentices have the possibility to experiment and gain experiences by deliberate error simulations

(Pro)renin receptor: subcellular localizations and functions

Since its first report in 1996, the concept of the so-called (Pro)renin receptor ((P)RR/ATP6ap2) has dramactically evolved from a receptor mediating cellular effects of (pro)renin, to a protein with more basic and potentially essential intracellular functions. Among the arguments urging to reconsider the role of (P)RR was the observation that its localization appears mainly intracellular, although this does not preclude potential functions at the cell surface. However, despite about 10 years of research boosted by the generation of genetically modified animal models, the basic mechanisms of action of this protein at the cellular level remain elusive. This review aims at discussing the functions described for (P)RR in relation to its subcellular localization(s)