Hurdles to the introduction of new therapies for immune-mediated kidney diseases.

Innovative immunotherapies continue to markedly benefit many disciplines in clinical medicine but disappointingly, these benefits have not translated to the treatment of kidney diseases despite encouraging findings from preclinical models of kidney dysfunction. This lack of progress in nephrology might relate to the unique biology of the kidney. More likely, this lack of progress relates to conceptual hurdles in the application of newer therapies to renal disease.

Oxalate-induced chronic kidney disease with its uremic and cardiovascular complications in C57BL/6 mice.

Chronic kidney disease (CKD) research is limited by the lack of convenient inducible models mimicking human CKD and its complications in experimental animals. We demonstrate that a soluble oxalate-rich diet induces stable stages of CKD in male and female C57BL/6 mice. Renal histology is characterized by tubular damage, remnant atubular glomeruli, interstitial inflammation, and fibrosis, with the extent of tissue involvement depending on the duration of oxalate feeding.

Links between coagulation, inflammation, regeneration, and fibrosis in kidney pathology.

Acute kidney injury (AKI) involves nephron injury leading to irreversible nephron loss, ie, chronic kidney disease (CKD). Both AKI and CKD are associated with distinct histological patterns of tissue injury, but kidney atrophy in CKD involves tissue remodeling with interstitial inflammation and scarring. No doubt, nephron atrophy, inflammation, fibrosis, and renal dysfunction are associated with each other, but their hierarchical relationships remain speculative.

Neutrophils, Dendritic Cells, Toll-Like Receptors, and Interferon-α in Lupus Nephritis.

Finding better treatments for lupus nephritis requires an understanding of the pathogenesis of the causative systemic disease, how this leads to kidney disease, and how lupus nephritis progresses to end-stage kidney disease. Here, we provide a brief conceptual overview on the related pathomechanisms. As a main focus we discuss in detail the roles of neutrophils, dendritic cells, Toll-like receptors, and interferon-α in the pathogenesis of lupus nephritis by separately reviewing their roles in extrarenal systemic autoimmunity and in intrarenal inflammation and immunopathology.

Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications.

Endothelial dysfunction is a central pathomechanism in diabetes-associated complications. We hypothesized a pathogenic role in this dysfunction of cathepsin S (Cat-S), a cysteine protease that degrades elastic fibers and activates the protease-activated receptor-2 (PAR2) on endothelial cells. We found that injection of mice with recombinant Cat-S induced albuminuria and glomerular endothelial cell injury in a PAR2-dependent manner.

PMA and crystal-induced neutrophil extracellular trap formation involves RIPK1-RIPK3-MLKL signaling.

Neutrophil extracellular trap (NET) formation contributes to gout, autoimmune vasculitis, thrombosis, and atherosclerosis. The outside-in signaling pathway triggering NET formation is unknown. Here, we show that the receptor-interacting protein kinase (RIPK)-1-stabilizers necrostatin-1 or necrostatin-1s and the mixed lineage kinase domain-like (MLKL)-inhibitor necrosulfonamide prevent monosodium urate (MSU) crystal- or PMA-induced NET formation in human and mouse neutrophils.

Unmet medical needs in lupus nephritis: solutions through evidence-based, personalized medicine.

Lupus nephritis (LN) remains a kidney disease with significant unmet medical needs despite extensive clinical and translational research over the past decade. These include the need to (i) predict the individual risk for LN in a patient with systemic lupus erythematosus, (ii) identify the best therapeutic option for an individual patient, (iii) distinguish chronic kidney damage from active immunologic kidney injury, (iv) develop efficient treatments with acceptable or no side effects and improve the design of randomized clinical trials so that effective drugs demonstrate efficacy. This review discusses the underlying reasons for these unmet medical needs and options of how to overcome them in the future.

The lymphotoxin β receptor is a potential therapeutic target in renal inflammation.

Accumulation of inflammatory cells in different renal compartments is a hallmark of progressive kidney diseases including glomerulonephritis (GN). Lymphotoxin β receptor (LTβR) signaling is crucial for the formation of lymphoid tissue, and inhibition of LTβR signaling has ameliorated several non-renal inflammatory models. Therefore, we tested whether LTβR signaling could also have a role in renal injury.

Necroinflammation in Kidney Disease.

The bidirectional causality between kidney injury and inflammation remains an area of unexpected discoveries. The last decade unraveled the molecular mechanisms of sterile inflammation, which established danger signaling via pattern recognition receptors as a new concept of kidney injury-related inflammation. In contrast, renal cell necrosis remained considered a passive process executed either by the complement-related membrane attack complex, exotoxins, or cytotoxic T cells.

Heterogeneous susceptibility for uraemic media calcification and concomitant inflammation within the arterial tree.

Background: End-stage renal disease (ESRD) is strongly associated with arterial calcification of the tunica media, decreased vascular compliance and sudden cardiac death. Here, we analysed the distribution pattern of uraemic media calcification and concomitant inflammation in mice and men.

Methods: Uraemia was induced in DBA/2 mice with high-phosphate diet.

The Diagnosis and Treatment of Systemic Lupus Erythematosus.

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with a prevalence of 36.7/100 000 in Germany and a female/male ratio of 4:1. The clinical course is variable, with a broad spectrum of organ manifestations; lupus nephritis develops in about half of all patients.

IL-3 contributes to development of lupus nephritis in MRL/lpr mice.

MRL/lpr mice develop a spontaneous autoimmune disease that closely resembles human systemic lupus erythematosus (SLE) with DNA autoantibodies, hypergammaglobulinemia, immune complex glomerulonephritis, and systemic vasculitis. Little is known about the role of IL-3 in SLE. In order to study this we analyzed the expression of IL-3 in murine lupus and determined whether blockade of IL-3 with a monoclonal antibody or injection of recombinant IL-3 affects lupus nephritis in MRL/lpr mice.

MDM2 beyond cancer: podoptosis, development, inflammation, and tissue regeneration.

Murine double minute (MDM)-2 is an intracellular molecule with diverse biological functions. It was first described to limit p53-mediated cell cycle arrest and apoptosis, hence, gain of function mutations are associated with malignancies. This generated a rationale for MDM2 being a potential therapeutic target in cancer therapy.

HSP90 inhibition as a means of radiosensitizing resistant, aggressive soft tissue sarcomas.

Radiotherapy is an essential part of multi-modal treatment for soft tissue sarcomas. Treatment failure is commonly attributed to radioresistance, but comprehensive analyses of radiosensitivity are not available, and suitable biomarkers or candidates for targeted radiosensitization are scarce. Here, we systematically analyzed the intrinsic radioresistance of a panel of soft tissue sarcoma cell lines, and extracted scores of radioresistance by principal component analysis (PCA).

Immunity in arterial hypertension: associations or causalities?

Numerous studies describe associations between markers of inflammation and arterial hypertension (aHT), but does that imply causality? Interventional studies that reduce blood pressure reduced also markers of inflammation, but does immunosuppression improve hypertension? Here, we review the available mechanistic data. Aberrant immunity can trigger endothelial dysfunction but is hardly ever the primary cause of aHT. Innate and adaptive immunity get involved once hypertension has caused vascular wall injury as immunity is a modifier of endothelial dysfunction and vascular wall remodelling.

Targeting the heat shock response in combination with radiotherapy: Sensitizing cancer cells to irradiation-induced cell death and heating up their immunogenicity.

Radiotherapy represents an essential treatment option for the majority of cancer patients in different stages of their disease. Physical achievements of the recent years led to the implementation of high precision treatment planning procedures, and image-guided dose delivery is current state of the art. Yet, radiotherapy still faces several limitations with cancer intrinsic radioresistance being a key driver of therapeutic failure.

Interleukin-22 in kidney injury and regeneration.

Interleukins have become well-known regulators of innate and adaptive immunity-related tissue inflammation. Recently, IL-22 has gained a lot of interest for its unique functions in maintaining and regaining epithelial integrity. IL-22 is exclusively secreted by different immune cell subsets, while IL-22 receptors are mainly expressed by epithelial cells.

Neutrophil Extracellular Trap-Related Extracellular Histones Cause Vascular Necrosis in Severe GN.

Severe GN involves local neutrophil extracellular trap (NET) formation. We hypothesized a local cytotoxic effect of NET-related histone release in necrotizing GN. In vitro, histones from calf thymus or histones released by neutrophils undergoing NETosis killed glomerular endothelial cells, podocytes, and parietal epithelial cells in a dose-dependent manner.

Limisphaera ngatamarikiensis gen. nov., sp. nov., a thermophilic, pink-pigmented coccus isolated from subaqueous mud of a geothermal hotspring.

A novel bacterial strain, NGM72.4(T), was isolated from a hot spring in the Ngatamariki geothermal field, New Zealand. Phylogenetic analysis based on 16S rRNA gene sequences grouped it into the phylum Verrucomicrobia and class level group 3 (also known as OPB35 soil group).

Cell cycle control in the kidney.

Proper control of the cell cycle is mandatory during homeostasis and disease. The balance of p53 and MDM2 integrates numerous signalling pathways to regulate the cell cycle, which is executed by multiple proteins including the cyclins, cyclin kinases and cyclin kinase inhibitors. Mutations or environmental factors that affect cell cycle control can lead to inappropriate hyperplasia or cancer as well as to cell loss and tissue atrophy.

Glomerular parietal epithelial cell activation induces collagen secretion and thickening of Bowman's capsule in diabetes.

The metabolic and hemodynamic alterations in diabetes activate podocytes to increase extracellular matrix (ECM) production, leading to thickening of the glomerular basement membrane (GBM). We hypothesized that diabetes would activate parietal epithelial cells (PECs) in a similar manner and cause thickening of Bowman's capsules. Periodic acid Schiff staining of human kidney biopsies of 30 patients with diabetic nephropathy (DN) revealed a significantly thicker Bowman's capsule as compared with 20 non-diabetic controls.

Lupus nephritis: from pathogenesis to targets for biologic treatment.

Background/aims: Lupus nephritis is an organ manifestation of systemic autoimmunity. Current treatment algorithms are still based on unselective immunosuppressive drugs. There is hope that highly selective biological drugs could be as or even more effective but less toxic.

Synchronized renal tubular cell death involves ferroptosis.

Receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis is thought to be the pathophysiologically predominant pathway that leads to regulated necrosis of parenchymal cells in ischemia-reperfusion injury (IRI), and loss of either Fas-associated protein with death domain (FADD) or caspase-8 is known to sensitize tissues to undergo spontaneous necroptosis. Here, we demonstrate that renal tubules do not undergo sensitization to necroptosis upon genetic ablation of either FADD or caspase-8 and that the RIPK1 inhibitor necrostatin-1 (Nec-1) does not protect freshly isolated tubules from hypoxic injury. In contrast, iron-dependent ferroptosis directly causes synchronized necrosis of renal tubules, as demonstrated by intravital microscopy in models of IRI and oxalate crystal-induced acute kidney injury.

Murine Double Minute-2 Prevents p53-Overactivation-Related Cell Death (Podoptosis) of Podocytes.

Murine double minute-2 (MDM2), an E3 ligase that regulates the cell cycle and inflammation, is highly expressed in podocytes. In podocyte injury, MDM2 drives podocyte loss by mitotic catastrophe, but the function of MDM2 in resting podocytes has not been explored. Here, we investigated the effects of podocyte MDM2 deletion in vitro and in vivo.