Discovery of a Small Molecule with an Inhibitory Role for RAB11.

RAB11, a pivotal RabGTPase, regulates essential cellular processes such as endocytic recycling, exocytosis, and autophagy. The protein was implicated in various human diseases, including cancer, neurodegenerative disorders, viral infections, and podocytopathies. However, a small-molecular inhibitor is lacking.

Surveillance in Children and Adolescents with von Hippel-Lindau (VHL)-Related Pheochromocytomas and Paragangliomas: A Survey of MET and Freiburg-VHL Registries in Germany.

Early identification of patients at risk with von Hippel-Lindau (VHL) syndrome-related pheochromocytoma and paraganglioma (PPGL) is crucial to prevent morbidity. We investigated the current surveillance recommendations in VHL-related PPGL in children and adolescents. German Pediatric Oncology and Hematology-Malignant Endocrine Tumor registry (GPOH-MET) and Freiburg-VHL registry (1996-2022).

Cyclin-dependent kinase 4 drives cystic kidney disease in the absence of mTORC1 signaling activity.

Progression of cystic kidney disease has been linked to activation of the mTORC1 signaling pathway. Yet the utility of mTORC1 inhibitors to treat patients with polycystic kidney disease remains controversial despite promising preclinical data. To define the cell intrinsic role of mTORC1 for cyst development, the mTORC1 subunit gene Raptor was selectively inactivated in kidney tubular cells lacking cilia due to simultaneous deletion of the kinesin family member gene Kif3A.

Linking Basement Membrane and Slit Diaphragm in Drosophila Nephrocytes.

Key Points: nephrocytes feature a special basement membrane that may serve to model joint function of the glomerular filtration barrier. Silencing of laminin and collagen IV genes reduced the density of slit diaphragms in nephrocytes, showing a direct effect of the matrix. Matrix receptor silencing phenocopied basement membrane disruption, indicating that the matrix guides slit diaphragm position through matrix receptors.

Non-antigen-specific Immunoadsorption Is a Risk Factor for Severe Postoperative Infections in ABO-Incompatible Kidney Transplant Recipients.

ABO-incompatible (ABOi) living kidney transplantation (KTx) is an established procedure to address the demand for kidney transplants with outcomes comparable to ABO-compatible KTx. Desensitization involves the use of immunoadsorption (IA) to eliminate preformed antibodies against the allograft. This monocentric retrospective study compares single-use antigen-selective Glycosorb ABO columns to reusable non-antigen-specific Immunosorba immunoglobulin adsorption columns regarding postoperative infectious complications and outcome.

Transcriptional regulation by the NSL complex enables diversification of IFT functions in ciliated versus nonciliated cells.

Members of the NSL histone acetyltransferase complex are involved in multiorgan developmental syndromes. While the NSL complex is known for its importance in early development, its role in fully differentiated cells remains enigmatic. Using a kidney-specific model, we discovered that deletion of NSL complex members KANSL2 or KANSL3 in postmitotic podocytes led to catastrophic kidney dysfunction.

Inversin (NPHP2) and Vangl2 are required for normal zebrafish cloaca formation.

Nephronophthisis (NPH), an autosomal recessive ciliopathy, results from mutations in more than 20 different genes (NPHPs). These gene products form protein complexes that regulate trafficking within the cilium, a microtubular structure that plays a crucial role in developmental processes. Several NPHPs, including NPHP2/Inversin, have been linked to extraciliary functions.

An alternative approach to assess ecotoxicological effects of agrochemical combinations used in Brazilian aquaculture farms.

Agrochemicals used for treating and preventing aquaculture diseases are usually present in combination with other compounds, and the toxicity resulting from their chemical interactions presents an important reason to assess the ecotoxicity of compound mixtures in view to better understanding the joint action of chemicals and avoiding their environmental impacts. In this study, we evaluated the acute aquatic ecotoxicity of several compounds used in Brazilian fish farming (Oxytetracycline [OXT], Trichlorfon [TRC], and BioFish® [BIO]), both individually and in binary and ternary mixtures. Initial test concentrations were prepared according to the recommended concentrations for aquaculture application, and from these, a geometric dilution series was tested on two important fresh water quality indicator species, the microcrustacean Daphnia magna and the bacterium Aliivibrio fischeri.

Nirmatrelvir/ritonavir treatment in SARS-CoV-2 positive kidney transplant recipients - a case series with four patients.

Background: Despite vaccination coronavirus disease 2019 (COVID-19)-associated mortality caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains high in kidney transplant recipients. Nirmatrelvir is a protease inhibitor with activity against SARS-CoV-2. Nirmatrelvir reduces the risk for mortality and hospitalization, which is approved for treating adults at risk for severe disease.

SCD5 Regulation by VHL Affects Cell Proliferation and Lipid Homeostasis in ccRCC.

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cancer, and inactivation of the VHL tumor suppressor gene is found in almost all cases of hereditary and sporadic ccRCCs. CcRCC is associated with the reprogramming of fatty acid metabolism, and stearoyl-CoA desaturases (SCDs) are the main enzymes controlling fatty acid composition in cells. In this study, we report that mRNA and protein expression of the stearoyl-CoA desaturase SCD5 is downregulated in -deficient cell lines.

Nephrotic Syndrome Gene Is Required for Endosomal Maturation and Nephrin Endocytosis in .

Background: Variants in cause nephrotic syndrome. TBC1D8B is a GTPase-activating protein for Rab11 (RAB11-GAP) that interacts with nephrin, but how it controls nephrin trafficking or other podocyte functions remains unclear.

Methods: We generated a stable deletion in and used microhomology-mediated end-joining for genome editing.

Histone Deacetylases Cooperate with NF-κB to Support the Immediate Migratory Response after Zebrafish Pronephros Injury.

Acute kidney injury (AKI) is commonly associated with severe human diseases, and often worsens the outcome in hospitalized patients. The mammalian kidney has the ability to recover spontaneously from AKI; however, little progress has been made in the development of supportive treatments. Increasing evidence suggest that histone deacetylases (HDAC) and NF-κB promote the pathogenesis of AKI, and inhibition of Hdac activity has a protective effect in murine models of AKI.

MARVEL domain containing CMTM4 affects CXCR4 trafficking.

The MARVEL proteins CMTM4 and CMTM6 control PD-L1, thereby influencing tumor immunity. We found that defective zebrafish slowed the development of the posterior lateral line (pLL) by altering the Cxcr4b gradient across the pLL primordium (pLLP). Analysis in mammalian cells uncovered that CMTM4 interacted with CXCR4, altering its glycosylation pattern, but did not affect internalization or degradation of CXCR4 in the absence of its ligand CXCL12.

Evaluation of Deceased Donor Kidney Transplantation in the Eurotransplant Senior Program in Comparison to Standard Allocation.

BACKGROUND The organ shortage and long waiting times have dramatically increased the age of potential kidney transplant recipients. The Eurotransplant Senior Program (ESP) was initiated to allocate kidneys from deceased donors aged ≥65 years to recipients with a comparable age independent of pre-transplant human leucocyte antigen (HLA) matching; however, parameters affecting the long-term benefits of this strategy remain poorly defined. MATERIAL AND METHODS We retrospectively evaluated outcome and risk factors for mortality in kidney recipients aged ≥65 years that were transplanted according to the ESP protocol relative to patients aged >50 years transplanted according to the Eurotransplant kidney allocation system (ETKAS) criteria at the University Freiburg Medical Center, Germany, between 2008 and 2018.

Control of Directed Cell Migration after Tubular Cell Injury by Nucleotide Signaling.

Acute kidney injury (AKI) is a common complication of severe human diseases, resulting in increased morbidity and mortality as well as unfavorable long-term outcomes. Although the mammalian kidney is endowed with an amazing capacity to recover from AKI, little progress has been made in recent decades to facilitate recovery from AKI. To elucidate the early repair mechanisms after AKI, we employed the zebrafish pronephros injury model.

Selective endocytosis controls slit diaphragm maintenance and dynamics in nephrocytes.

The kidneys generate about 180 l of primary urine per day by filtration of plasma. An essential part of the filtration barrier is the slit diaphragm, a multiprotein complex containing nephrin as major component. Filter dysfunction typically manifests with proteinuria and mutations in endocytosis regulating genes were discovered as causes of proteinuria.

Clock genes rescue nphp mutations in zebrafish.

The zebrafish pronephros model, using morpholino oligonucleotides (MO) to deplete target genes, has been extensively used to characterize human ciliopathy phenotypes. Recently, discrepancies between MO and genetically defined mutants have questioned this approach. We analyzed zebrafish with mutations in the nphp1-4-8 module to determine the validity of MO-based results.

mTOR-Dependent Autophagy Regulates Slit Diaphragm Density in Podocyte-like Nephrocytes.

Both mTOR signaling and autophagy are important modulators of podocyte homeostasis, regeneration, and aging and have been implicated in glomerular diseases. However, the mechanistic role of these pathways for the glomerular filtration barrier remains poorly understood. We used nephrocytes as an established podocyte model and found that inhibition of mTOR signaling resulted in increased spacing between slit diaphragms.

Effect of Cyclophosphamide and Glucocorticoid Therapy in IgA Nephropathy: A Single-Center Retrospective Analysis.

Background: IgA nephropathy (IgAN) is the most common primary glomerulonephritis in adults, which causes ESKD in ≤45% of patients in the long term. The optimal therapeutic approach remains undetermined. In this study, we report the results of a single-center retrospective analysis of patients with IgAN.

Microridge-like structures anchor motile cilia.

Several tissues contain cells with multiple motile cilia that generate a fluid or particle flow to support development and organ functions; defective motility causes human disease. Developmental cues orient motile cilia, but how cilia are locked into their final position to maintain a directional flow is not understood. Here we find that the actin cytoskeleton is highly dynamic during early development of multiciliated cells (MCCs).

α-Parvin Defines a Specific Integrin Adhesome to Maintain the Glomerular Filtration Barrier.

Background: The cell-matrix adhesion between podocytes and the glomerular basement membrane is essential for the integrity of the kidney's filtration barrier. Despite increasing knowledge about the complexity of integrin adhesion complexes, an understanding of the regulation of these protein complexes in glomerular disease remains elusive.

Methods: We mapped the composition of the podocyte integrin adhesome.