• FDA
• glomerulus
• kidney
• podocyte
• podocytopathies
• therapeutics

• Humans
• Podocytes
• Pharmaceutical Preparations
• Drug Repositioning
• Kidney
• Renal Insufficiency, Chronic/drug therapy

• R01 DK056799 NIDDK NIH HHS
• R01 DK097598 NIDDK NIH HHS
• R01 DK128204 NIDDK NIH HHS
• UC2 DK126006 NIDDK NIH HHS

Diabetes mellitus is considered a leading contributor to severe coronavirus disease 2019 (COVID-19).

To characterize differences between hospitalized diabetic patients with vs without COVID-19, and parameters associated with COVID-19 severity for prediction.

This case-control study included 209 patients with type 2 diabetic mellitus hospitalized at the Galilee Medical Center (Nahariya, Israel) and recruited between September 2020 and May 2021, 65 patients with COVID-19 infection in dedicated wards and 144 COVID-19-negative patients in internal medicine wards hospitalized due to other reasons. Clinical parameters - including age, type of antiglycemic medications, presence of retinopathy, smoking history, body mass index (BMI), glycosylated hemoglobin, maximum neutrophil:lymphocyte ratio (NLR_max), C-reactive protein (CRP), estimated glomerular filtration rate (eGFR), and albumin (blood and urine) - were compared between the two primary patient groups, and then between COVID-19-negative patients hospitalized due to infectious vs non-infectious disease. Finally, we explored which parameters were associated with severe COVID-19 pneumonia.

COVID-19-negative patients were older (63.9 ± 9.9 vs 59.8 ± 9.2, P = 0.005), and had longer duration of diabetes (P = 0.031), lower eGFR (P = 0.033), higher albumin (P = 0.026), lower CRP (P < 0.001), greater smoking prevalence (P < 0.001), and more baseline albuminuria (54.9% vs 30.8%, P = 0.005) at admission; 70% of COVID-19 patients with albuminuria had moderate-range albuminuria (albumin:creatinine 30-300 mg/g). Most of the patients with albuminuria had chronic kidney disease stage II (CKD II). Oral antiglycemic therapies were not significantly different between the two groups. Multivariable logistic regression showed that higher BMI was significantly associated with severe COVID-19 (OR 1.24, 95%CI: 1.01-1.53, P = 0.04), as was higher NLR_max (OR 1.2, 95%CI: 1.06-1.37, P = 0.005). Surprisingly, pre-hospitalization albuminuria, mostly moderate-range, was associated with reduced risk (OR 0.09, 95%CI: 0.01-0.62, P = 0.015). Moderate-range albuminuria was not associated with bacterial infections.

Moderate-range albuminuria in COVID-19-positive diabetic patients with CKD II is associated with less severe COVID-19. Further studies should explore this potential biomarker for risk of COVID-19-related deterioration and early interventions.

• Diabetes mellitus
• COVID-19
• Albuminuria
• Severity
• Chronic kidney disease
• Immunomodulation

The COVID-19 pandemic has put a tremendous stress on the medical community over the last two years. Managing the infection proved a lot more difficult after several research communities started to recognize the long-term effects of this disease. The cellular receptor for the virus was identified as angiotensin-converting enzyme-2 (ACE2), a molecule responsible for a wide array of processes, broadly variable amongst different organs. Angiotensin (Ang) 1-7 is the product of Ang II, a decaying reaction catalysed by ACE2. The effects observed after altering the level of ACE2 are essentially related to the variation of Ang 1-7. The renin-angiotensin-aldosterone system (RAAS) is comprised of two main branches, with ACE2 representing a crucial component of the protective part of the complex. The ACE2/Ang (1-7) axis is well represented in the testis, heart, brain, kidney, and intestine. Infection with the novel SARS-CoV-2 virus determines downregulation of ACE2 and interrupts the equilibrium between ACE and ACE2 in these organs. In this review, we highlight the link between the local effects of RAAS and the consequences of COVID-19 infection as they arise from observational studies.

A disease outbreak in December 2019, caused by a novel coronavirus SARS-CoV-2, was named COVID-19. SARS-CoV-2 infects cells from the upper and lower respiratory tract system and is transmitted by inhalation or contact with infected droplets. Common clinical symptoms include fatigue, fever, and cough, but also shortness of breath and lung abnormalities. Still, some 5% of SARS-CoV-2 infections progress to severe pneumonia and acute respiratory distress syndrome (ARDS), with pulmonary edema, acute kidney injury, and/or multiple organ failure as important consequences, which can lead to death. The innate immune system recognizes viral RNAs and triggers the expression of interferons (IFN). IFNs activate anti-viral effectors and components of the adaptive immune system by activating members of the STAT and IRF families that induce the expression of IFN-stimulated genes (ISG)s. Among other coronaviruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV, common strategies have been identified to antagonize IFN signaling. This typically coincides with hyperactive inflammatory host responses known as the “cytokine storm” that mediate severe lung damage. Likewise, SARS-CoV-2 infection combines a dysregulated IFN response with excessive production of inflammatory cytokines in the lungs. This excessive inflammatory response in the lungs is associated with the local recruitment of immune cells that create a pathogenic inflammatory loop. Together, it causes severe lung pathology, including ARDS, as well as damage to other vulnerable organs, like the heart, spleen, lymph nodes, and kidney, as well as the brain. This can rapidly progress to multiple organ exhaustion and correlates with a poor prognosis in COVID-19 patients. In this review, we focus on the crucial role of different types of IFN that underlies the progression of SARS-CoV-2 infection and leads to immune cell hyper-activation in the lungs, exuberant systemic inflammation, and multiple organ damage. Consequently, to protect from systemic inflammation, it will be critical to interfere with signaling cascades activated by IFNs and other inflammatory cytokines. Targeting members of the STAT family could therefore be proposed as a novel therapeutic strategy in patients with severe COVID-19.

• COVID – 19
• STAT signaling
• Statinhib
• immune hyperactivation
• interferon response
• multiple organ damage
• therapy

In systemic lupus erythematosus (SLE), detection of interferon-β (IFNβ) in B cells was found to be most prominent in patients with high anti-Smith (Sm) and renal disease, but a mechanistic connection was not clear. The objective of the present study is to determine the association of IFNβ in peripheral blood naïve B cells with the histopathological features of lupus nephritis (LN).

The percentage of IFNβ⁺ cells in IgD⁺CD27⁻ naïve CD19⁺ B cells (B cell IFNβ) among peripheral blood mononuclear cells (PBMCs) from 80 SLE patients were analyzed using flow cytometry. Serological and clinical data were collected. The correlations of B cell IFNβ with LN classification and with histopathological findings (light, electron, and immunofluorescence [IF] microscopic analyses for deposition of IgM, IgG, IgA, C1q, and C3) were determined in 23 available biopsy specimens.

B cell IFNβ is positively associated with anti-Sm (p = 0.001), anti-DNA (p = 0.013), and LN (p < 0.001) but was negatively associated with oral/nasal ulcer (p = 0.003) and photosensitivity (p = 0.045). B cell IFNβ positively correlated with immune complex (IC) deposit in the glomerular basement membrane (GBM) (p = 0.002) but not in the mesangial (p = 0.107) or tubular region (p = 0.313). Patients with high B cell IFNβ had statistically increased development of the proliferative LN (Classes III, IV and/or V), compared to patients with low B cell IFNβ (p < 0.0001). Histopathological features positively associated with increased B cell IFNβ included active glomerular lesions as determined by fibrocellular crescents (p = 0.023), chronic glomerular lesions indicated by segmental sclerosis (p = 0.033), and a membranous pattern of renal damage indicated by spike/holes (p = 0.015).

B cell IFNβ correlates with history of severe LN, glomerular basement membrane (GBM) IC deposition, and anatomical features of both active and chronic glomerular lesions.

• Autoantibodies
• B cell interferon beta
• Lupus nephritis
• Systemic lupus erythematosus

• kidney
• acute kidney injury
• sars-cov-2
• infectious diseases

• Acute Kidney Injury/physiopathology
• Acute Kidney Injury/virology
• Adaptive Immunity/physiology
• Biopsy
• COVID-19/physiopathology
• Complement System Proteins
• Drug-Related Side Effects and Adverse Reactions
• Endothelium, Vascular/physiopathology
• Extracorporeal Membrane Oxygenation
• Hematuria/physiopathology
• Humans
• Immunity, Humoral/physiology
• Immunity, Innate/physiology
• Immunosenescence
• Inflammation/physiopathology
• Inflammation/virology
• Interferon Type I/physiology
• Kidney/pathology
• Kidney/virology
• Proteinuria/physiopathology
• Severity of Illness Index
• Viral Load

Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE) and a major risk factor for morbidity and mortality. The abundant cell-free nucleic (DNA/RNA) in SLE patients, especially dsDNA, is a key substance in the pathogenesis of SLE and LN. The deposition of DNA/RNA-immune complexes (DNA/RNA-ICs) in the glomerulus causes a series of inflammatory reactions that lead to resident renal cell disturbance and eventually renal fibrosis. Cell-free DNA/RNA is the most effective inducer of type I interferons (IFN-I). Resident renal cells (rather than infiltrating immune cells) are the main source of IFN-I in the kidney. IFN-I in turn damages resident renal cells. Not only are resident renal cells victims, but also participants in this immunity war. However, the mechanism for generation of IFN-I in resident renal cells and the pathological mechanism of IFN-I promoting renal fibrosis have not been fully elucidated. This paper reviews the latest epidemiology of LN and its development process, discusses the mechanism for generation of IFN-I in resident renal cells and the role of IFN-I in the pathogenesis of LN, and may open a new perspective for the treatment of LN.

• IFN-I
• fibrosis
• lupus nephritis
• nucleic acid sensors
• pathogenesis
• renal resident cells

• genetic
• lupus erythematosus
• lupus nephritis
• polymorphism
• systemic

• Genetic Predisposition to Disease
• Humans
• Lupus Erythematosus, Systemic
• Lupus Nephritis
• Toll-Like Receptor 1
• Toll-Like Receptors

• the Swedish Rheumatism Association and King Gustav V’s 80-year Foundation
• Uppsala Universitet
• the Swedish Society of Medicine and the Ingegerd Johansson donation.
• Swedish Research Council for Medicine and Health

• TLR8
• chronic kidney disease
• obstructed and collateral kidney
• obstructive nephropathy
• podocyte

• Age Factors
• Animals
• Cells, Cultured
• Cytokines/genetics
• Cytokines/metabolism
• Disease Models, Animal
• Endothelial Cells/metabolism
• Endothelial Cells/ultrastructure
• Kidney Diseases/genetics
• Kidney Diseases/metabolism
• Kidney Diseases/pathology
• Kidney Glomerulus/metabolism
• Kidney Glomerulus/ultrastructure
• Ligands
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Mice, Inbred C57BL
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Microfilament Proteins/genetics
• Microfilament Proteins/metabolism
• Podocytes/metabolism
• Podocytes/ultrastructure
• Signal Transduction
• Toll-Like Receptor 8/metabolism
• Mice

• Biomarker
• CD80
• Glomerular endothelial cell
• Nephrotic syndrome
• Podocyte

Damage to and loss of glomerular podocytes has been identified as the culprit lesion in progressive kidney diseases. Here, we combine mass spectrometry-based proteomics with mRNA sequencing, bioinformatics, and hypothesis-driven studies to provide a comprehensive and quantitative map of mammalian podocytes that identifies unanticipated signaling pathways. Comparison of the in vivo datasets with proteomics data from podocyte cell cultures showed a limited value of available cell culture models. Moreover, in vivo stable isotope labeling by amino acids uncovered surprisingly rapid synthesis of mitochondrial proteins under steady-state conditions that was perturbed under autophagy-deficient, disease-susceptible conditions. Integration of acquired omics dimensions suggested FARP1 as a candidate essential for podocyte function, which could be substantiated by genetic analysis in humans and knockdown experiments in zebrafish. This work exemplifies how the integration of multi-omics datasets can identify a framework of cell-type-specific features relevant for organ health and disease.

•

Deep proteome and transcriptome analyses of native podocytes unravel druggable targets

• end-stage renal disease
• focal segmental glomerulosclerosis
• hereditary nephrotic syndrome
• kinase
• metabolism
• proteinuria
• proteostasis
• pulse SILAC
• slit diaphragm
• systems biology

• BXSB/MpJ-Yaa mice
• Toll-like receptor 9
• kidney
• membranoproliferative glomerulonephritis
• podocyte

• CD80
• Lipopolysaccharide
• Minimal change disease
• Neph1
• Podocytes
• TNFα

• Animals
• Disease Models, Animal
• Female
• Humans
• Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors
• Lupus Erythematosus, Systemic/drug therapy
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Myeloid Differentiation Factor 88/physiology
• Prednisolone/therapeutic use
• Toll-Like Receptor 7/physiology
• Toll-Like Receptor 9/physiology

Transient albuminuria induced by pathogen-associated molecular patterns (PAMPs) in mice through engagement of Toll-like receptors (TLRs) is widely studied as a partial model for some forms of human nephrotic syndrome (NS). In addition to TLRs, CD80 has been shown to be essential for PAMP-mediated albuminuria. However, the mechanistic relationships between TLRs, CD80 and albuminuria remain unclear. Here, we show that albuminuria and CD80-uria induced in mice by many TLR ligands are dependent on the expression of TLRs and their downstream signalling intermediate MyD88 exclusively in hematopoietic cells and, conversely, on CD80 expression exclusively in non-hematopoietic cells. TNFα is crucial for TLR-mediated albuminuria and CD80-uria, and induces CD80 expression in cultured renal podocytes. IL-10 from hematopoietic cells ameliorates TNFα production, albuminuria and CD80-uria but does not prevent TNFα-mediated induction of podocyte CD80 expression. Chitohexaose, a small molecule originally of parasite origin, mediates TLR4-dependent anti-inflammatory responses, and blocks TLR-mediated albuminuria and CD80-uria through IL-10. Thus, TNFα is a prominent mediator of renal CD80 induction and resultant albuminuria in this model, and small molecules modulating TLR-mediated inflammatory activation might have contributory or adjunct therapeutic potential in some contexts of NS development.

Summary: Systemic TNFα mediates myeloid cell and podocyte cross-talk to cause LPS-induced mouse microalbuminuria, a partial model of human nephrotic syndrome, pointing to potential adjunct therapeutic approaches.

• CD80
• IL-10
• Proteinuria
• TLR
• TNFα

• ARF
• GN
• immunology and pathology

• Acute Kidney Injury/immunology
• Animals
• Fibrosis/immunology
• Humans
• Inflammasomes/physiology
• Inflammation/immunology
• Inflammation Mediators/physiology
• Kidney/injuries
• Kidney/pathology
• Kidney/physiology
• Kidney Diseases/immunology
• Regeneration/physiology
• Renal Insufficiency, Chronic/immunology
• Toll-Like Receptors/physiology