Resident Renal Cells Research Articles

Integrated temporal transcriptional and epigenetic single-cell analysis reveals the intrarenal immune characteristics in an early-stage model of IgA nephropathy during its acute injury

RationaleKidney inflammation plays a crucial role in the pathogenesis of IgA nephropathy (IgAN), yet the specific phenotypes of immune cells involved in disease progression remain incompletely understood. Utilizing joint profiling through longitudinal single-cell RNA-sequencing (scRNAseq) and single-cell assay for transposase-accessible chromatin sequencing (scATACseq) can provide a comprehensive framework for elucidating the development of cell subset diversity and how chromatin accessibility regulates transcription.ObjectiveWe aimed to characterize the dynamic immune cellular landscape at a high resolution in an early IgAN mouse model with acute kidney injury (AKI).Methods and resultsA murine model was utilized to mimic 3 immunological states –”immune stability (IS), immune activation (IA) and immune remission (IR)” in early human IgAN-associated glomerulopathy during AKI, achieved through lipopolysaccharide (LPS) injection. Urinary albumin to creatinine ratio (UACR) was measured to further validate the exacerbation and resolution of kidney inflammation during this course. Paired scRNAseq and scATACseq analysis was performed on CD45+ immune cells isolated from kidney tissues obtained from CTRL (healthy vehicle), IS, IA and IR (4 or 5 mice each). The analyses revealed 7 major cell types and 24 clusters based on 72304 single-cell transcriptomes, allowing for the identification and characterization of various immune cell types within each cluster. Our data offer an impartial depiction of the immunological characteristics, as the proportions of immune cell types fluctuated throughout different stages of the disease. Specifically, these analyses also revealed novel subpopulations, such as a macrophage subset (Nlrp1b Mac) with distinct epigenetic features and a unique transcription factor motif profile, potentially exerting immunoregulatory effects, as well as an early subset of Tex distinguished by their effector and cytolytic potential (CX3CR1-transTeff). Furthermore, in order to investigate the potential interaction between immune cells and renal resident cells, we conducted single-cell RNA sequencing on kidney cells obtained from a separate cohort of IS and IA mice without isolating immune cells. These findings underscored the diverse roles played by macrophages and CD8+ T cells in maintaining homeostasis of endothelial cells (ECs) under stress.ConclusionsThis study presents a comprehensive analysis of the dynamic changes in immune cell profiles in a model of IgAN, identifying key cell types and their roles and interactions. These findings significantly contribute to the understanding of the pathogenesis of IgAN and may provide potential targets for therapeutic intervention.

Plant natural products: A lead for nephroprotection

An extremely dangerous side effect of type I and type II diabetes is diabetic nephropathy (DN). From the early microproteinuria to end-stage renal failure, it progresses. About one in three diabetics in the US suffer from diabetic nephropathy. Chronic hyperglycemia is the primary cause of diabetic ketoacidosis. Hyperglycemia (HG) has the potential to cause humoral mediators and cytokines to be produced by both resident and non-resident renal cells. These substances may interfere with cell growth, alter renal cell and tissue phenotype and function, interact with proteins, produce advanced glycation end products (AGEs), damage tubules and glomeruli, and ultimately cause kidney disease. Poor blood glucose management is thus a significant risk factor for the onset of DN. An alternate course of treatment for DN may use extracts from herbal remedies. Medicinal plants' bioactive components stop DN from progressing. Attention has to be paid to the role that traditional herbs and medications play in the treatment of diabetic nephropathy, particularly in India where several fruits and herbs are believed to provide health benefits. Natural compounds influence the KEAP1/Nrf2/ARE and NFB pathways in addition to having antioxidant and anti-inflammatory properties. The efficacy of entire herbs, plants, or seeds, together with their active components, in treating diabetic nephropathy was investigated in preclinical research. Natural compounds are biologically active substances that come from natural sources and are beneficial for treating specific illnesses. Numerous natural substances, such as glycosides, polysaccharides, terpenoids, alkaloids, flavonoids, and polyphenols, have been shown to enhance DN. The exorbitant expenses associated with contemporary medications suggest that other approaches are necessary for improved DN treatment. Future research on herbal remedies may provide a natural key to open a pharmacy for diabetologists. Keywords: Diabetic nephropathy; nephroprotective plant; herbal compounds, bioactive compound

Role of the Anaphylatoxin Receptor C5aR2 in Angiotensin II-Induced Hypertension and Hypertensive End-Organ Damage.

Complement activation may facilitate hypertension through its effects on immune responses. The anaphylatoxin C5a, a major inflammatory effector, binds to the C5a receptors 1 and 2 (C5aR1, C5aR2). We have recently shown that C5aR1-/- mice have reduced hypertensive renal injury. The role of C5aR2 in hypertension is unknown. For examination of C5aR2 expression on infiltrating and resident renal cells a tandem dye Tomato-C5aR2 knock-in reporter mouse was used. Human C5aR2 expression was analyzed in a single-cell RNAseq data set from the kidneys of hypertensive patients. Finally, we examined the effect of angiotensin II-induced hypertension in C5aR2-deficient mice. Flow cytometric analysis of leukocytes isolated from kidneys of the reporter mice showed that dendritic cells are the major C5aR2-expressing population (34%) followed by monocyte/macrophages (30%) and neutrophils (14%). Using confocal microscopy C5aR2 was not detected in resident renal or cardiac cells. In the human kidney, C5aR2 was also mainly found in monocytes, macrophages, and dendritic cells with a significantly higher expression in hypertension (P < 0.05). Unilateral nephrectomy was performed followed by infusion of Ang II (0.75 ng/g/min) and a high salt diet in wildtype (n = 18) and C5aR2-deficient mice (n = 14). Blood pressure, renal injury (albuminuria, glomerular filtration rate, glomerular and tubulointerstitial injury, inflammation), and cardiac injury (cardiac fibrosis, heart weight, gene expression) did not differ between hypertensive wildtype and C5aR2-/- mice. In summary, C5aR2 is mainly expressed in myeloid cells in the kidney in mice and humans but its deficiency has no effect on Ang II-induced hypertensive injury.

New insights into the role of immunity and inflammation in diabetic kidney disease in the omics era.

Diabetic kidney disease (DKD) is becoming the leading cause of chronic kidney disease, especially in the industrialized world. Despite mounting evidence has demonstrated that immunity and inflammation are highly involved in the pathogenesis and progression of DKD, the underlying mechanisms remain incompletely understood. Substantial molecules, signaling pathways, and cell types participate in DKD inflammation, by integrating into a complex regulatory network. Most of the studies have focused on individual components, without presenting their importance in the global or system-based processes, which largely hinders clinical translation. Besides, conventional technologies failed to monitor the different behaviors of resident renal cells and immune cells, making it difficult to understand their contributions to inflammation in DKD. Recently, the advancement of omics technologies including genomics, epigenomics, transcriptomics, proteomics, and metabolomics has revolutionized biomedical research, which allows an unbiased global analysis of changes in DNA, RNA, proteins, and metabolites in disease settings, even at single-cell and spatial resolutions. They help us to identify critical regulators of inflammation processes and provide an overview of cell heterogeneity in DKD. This review aims to summarize the application of multiple omics in the field of DKD and emphasize the latest evidence on the interplay of inflammation and DKD revealed by these technologies, which will provide new insights into the role of inflammation in the pathogenesis of DKD and lead to the development of novel therapeutic approaches and diagnostic biomarkers.

Cell-cell communication in kidney fibrosis.

Kidney fibrosis is a common outcome of a wide variety of chronic kidney diseases, in which virtually all kinds of renal resident and infiltrating cells are involved. As such, well-orchestrated intercellular communication is of vital importance in coordinating complex actions during renal fibrogenesis. Cell-cell communication in multicellular organisms is traditionally assumed to be mediated by direct cell contact or soluble factors, including growth factors, cytokines and chemokines, through autocrine, paracrine, endocrine and juxtacrine signaling mechanisms. Growing evidence also demonstrates that extracellular vesicles, lipid bilayer-encircled particles naturally released from almost all types of cells, can act as a vehicle to transfer a diverse array of biomolecules including proteins, mRNA, miRNA and lipids to mediate cell-cell communication. We recently described a new mode of intercellular communication via building a special extracellular niche by insoluble matricellular proteins. Kidney cells, upon injury, produce and secrete different matricellular proteins, which incorporate into the local extracellular matrix network, and regulate the behavior, trajectory and fate of neighboring cells in a spatially confined fashion. This extracellular niche-mediated cell-cell communication is unique in that it restrains the crosstalk between cells within a particular locality. Detailed delineation of this unique manner of intercellular communication will help to elucidate the mechanism of kidney fibrosis and could offer novel insights in developing therapeutic intervention.

(5R)-5-hydroxytriptolide ameliorates diabetic kidney damage by inhibiting macrophage infiltration and its cross-talk with renal resident cells

ObjectiveDiabetic nephropathy (DN) is the main cause of end-stage renal disease, and there are no targeted treatment options at present. The efficacy of the new immunosuppressive drug (5R)-5-hydroxytriptolide (LLDT8) in improving kidney inflammation has been demonstrated in multiple studies. The present study was intended to investigate the preventive and therapeutic effects of LLDT8 on DN and to reveal its potential pharmacological mechanisms. MethodsThe effects of LLDT8 on liver and kidney functions, and urine microprotein of Streptozotocin (STZ) induced DN mice were detected. The protective effect of LLDT8 on the kidney tissue was observed by pathological staining and transmission electron microscopy. Cell culture experiments were performed to detect the effects of LLDT8 on the expression of chemokines and epithelial-mesenchymal transition (EMT) in high glucose-induced TCMK1 cells using real-time polymerase chain reaction (RT-PCR) and western blot (WB) techniques and to detect the influence of LLDT8 on the secretion of pro-inflammatory and pro-fibrotic factors in high glucose-induced RAW264.7 cells. ResultsIn animal experiments, treatment with high-dose LLDT8 (0.25 mg/kg/2d) reduced 24 h urinary albumin excretion, improved structural kidney damage, and delayed fibrosis progression in DN mice. Immunofluorescence results showed that LLDT8 intervention reduced macrophage infiltration in kidney tissues of DN mice. PCR and WB results of kidney tissues showed reduced expressions of chemokines CCL2 and M-CSF1 in the LLDT8 intervention group compared to the DN group. In cellular assays, LLDT8 treatment reduced chemokine secretion in high glucose-induced TCMK1 cells, but had no effect on EMT of TCMK1 cells. LLDT8 treatment reduced the secretion of pro-inflammatory and pro-fibrotic factors in high glucose-induced RAW264.7 cells. ConclusionsThe present study suggests that LLDT8 could effectively inhibit the secretion of pro-inflammatory and pro-fibrotic factors by macrophages, which could alleviate high glucose-induced renal tissue injury and slow down the process of tissue fibrosis and DN.

Single-cell transcriptomics uncover hub genes and cell–cell crosstalk in patients with hypertensive nephropathy

Hypertensive nephropathy (HTN) is one of the leading causes of end-stage renal disease, yet the molecular mechanisms are still unknown. To explore novel mechanisms and gene targets for HTN, the gene expression profiles of renal biopsy samples obtained from 2 healthy living donor controls and 5 HTN patients were determined by single-cell RNA sequencing. Key hub genes expression were validated by the Nephroseq v5 platform. The HTN endothelium upregulated cellular adhesion genes (ICAM2 and CEACAM1), inflammatory genes (ETS2 and IFI6) and apoptosis related genes (CNN3). Proximal tubules in HTN highly expressed hub genes including BBOX1, TPM1, TMSB10, SDC4, and NUP58, which might be potential novel targets for proximal tubular injury. The upregulated genes in tubules of HTN were mainly participating in inflammatory signatures including IFN-γ signature, NF-κB signaling, IL-12 signaling and Wnt signaling pathway. Receptor-ligand interaction analysis indicated potential cell–cell crosstalk between endothelial cells or mesangial cells with other renal resident cells in HTN. Together, our data identify a distinct cell-specific gene expression profile, pathogenic inflammatory signaling and potential cell–cell communications between endothelial cells or mesangial cells with other renal resident cells in HTN. These findings may provide a promising novel landscape for mechanisms and treatment of human HTN.

Abstract 014: Loss Of Resident Innate Immune Cells Prevents Salt-Induced Increases In Renal CD8 + T Cells

Hypertension is associated with an increase in pro-inflammatory cytokines and immune cells. Resident renal dendritic cells (rDCs) form an intricate network within the kidney. DCs can activate and recruit immune cells, as well as secrete pro-inflammatory cytokines. We previously showed that loss of renal DCs (rDC-depletion) prevents salt-sensitive hypertension and reduces intra-renal cytokines. We hypothesize that rDC-depletion alters the salt-induced immune cell profile within the kidney. To test this hypothesis, male mice lacking a functional CX 3 CR 1 chemokine receptor (CX 3 CR 1 - EGFP+/+ ) or wild-type (Wt, C57Bl6) were used. CX 3 CR 1 is required for DC localization to the kidney; thus, these mice are renal DC-depleted. Mice were fed HS (4%) or normal chow (NC) for 6 days; kidneys harvested, digested and FACS analysis performed on total immune cell populations (n=4 Wt &amp; rDC-depleted). Cells were gated on: CD45, MHCII, Ly6C, CD11c, CD11b, CCR2, CD3, CD8, CD4, F4/F80, NK1.1, XCR1, B220, CD64, Ly6G, CD86 and CX 3 CR 1 . Data were analyzed as a percent of total immune cells (CD45 + ). HS feeding increased CD8 + T cells (7.9% ± 0.3 vs . 4.2% ± 0.4 Wt NC, ***p&lt;0.001), while reducing classical DC1 cells (1.7% ± 0.2 vs . 3.4% ± 0.3 Wt NC, **p&lt;0.01). This increase in CD8 + T cell population was prevented in rDC-depleted mice (4.9% ± 0.4 vs . 4.9% ± 0.5 rDC NC). We observed no CD4 + T cell differences due to either HS or with rDC-depletion. Interestingly, NK cells were increased in rDC-depleted mice at baseline (1.8 fold, ***p&lt;0.001), and were normalized following HS feeding. In HS-fed mice, classical DC2 cells were also trending towards a decrease in rDC-depleted kidneys as compared to Wt. Here, we show that rDC-depletion prevents the salt-induced increases seen in renal CD8 + T cells. Our data previously showed early salt- and blood pressure-induced increases in cytokines, such as IL-27 and IL-6, that were similarly reduced in rDC-depleted mice. These data suggest that resident innate immune cells may be compulsory for the immediate response to increased dietary salt by increasing pro-inflammatory cytokines and recruitment of cytotoxic T cells, and may be crucial for the pathogenesis of salt-sensitive hypertension.

Expression of interferon-stimulated gene 20 (ISG20), an antiviral effector protein, in glomerular endothelial cells: possible involvement of ISG20 in lupus nephritis

Background In addition to regulating the antiviral response, increased expression of Toll-like receptor 3 (TLR3) in resident renal cells plays a role in developing some forms of glomerulonephritis. TLR3 activation leads to type I interferon (IFN) production, which induces the expression of IFN-stimulated genes (ISGs). However, the role of ISG20 expression in resident renal cells remains unclear. Methods Cultured normal human glomerular endothelial cells (GECs) were treated with polyinosinic-polycytidylic acid (poly IC), Escherichia coli lipopolysaccharide (LPS), R848, and CpG (TLR3, TLR4, TLR7, and TLR9 agonists, respectively). The mRNA levels of ISG20, CX3CL1/fractalkine, and CXCL10/IP-10 were measured by quantitative reverse transcription-polymerase chain reaction. ISG20 protein expression was assessed by Western blotting. RNA interference was used to knockdown IFN-β and ISG20 expression. CX3CL1 protein levels were assessed by enzyme-linked immunosorbent assay. We performed immunofluorescence to examine endothelial ISG20 expression in biopsy specimens from patients with lupus nephritis (LN). Results In GECs, the expression of ISG20 mRNA and protein was increased by polyIC, not by LPS, R848, or CpG treatment. Moreover, ISG20 knockdown prevented poly IC-induced CX3CL1 expression but had no effect on CXCL10 expression. Intense endothelial ISG20 immunoreactivity was observed in biopsy specimens obtained from patients with proliferative LN. Conclusion In GECs, ISG20 was regulated via TLR3 but not via TLR4, TLR7, or TLR9 signaling. Moreover, ISG20 was involved in regulating CX3CL1 production. In addition to regulating antiviral innate immunity, ISG20 may act as a mediator of CX3CL1 production, thereby inducing glomerular inflammation, particularly in patients with LN.

DEFICIENCY OF COMPLEMENT C3A AND C5A RECEPTORS DOES NOT PREVENT ANGIOTENSIN II–INDUCED HYPERTENSION AND HYPERTENSIVE END ORGAN DAMAGE

Objective: Complement activation may play an important role in pathophysiology of hypertension and associated end organ damage through its effect on tissue integrity and immune responses. The anaphylatoxins C3a and C5a are highly active effectors of the complement system operating through binding to their receptors C3a3R and C5aR1. Recently it was suggested that regulatory T cells (Tregs) are downregulated in hypertension and that combined deficiency of C3aR and C5aR1 in lymphocytes upregulates Tregs and heals hypertension (Circ Res 122: 970-983, 2018). Design and method: To further address the role of C3aR, C5aR1 and Tregs in human and murine hypertension we used data from the European Renal cDNA Bank, renal single cell sequencing and renal immunohistochemistry of hypertensive patients. Results: Expression of C3aR and C5aR1 was mainly found in myeloid cells and almost absent in lymphocytes and resident renal cells. An increased expression of C3aR, C5aR1 as well as forkhead box protein 3 (FoxP3), a known marker for Tregs, was found in the kidney in hypertension. Next we determined whether C3aR deficiency or C3aR/C5aR1 double deficiency decreases blood pressure and hypertensive injury in angiotensin (Ang) II infused mice. No difference was found for blood pressure, renal injury (glomerular filtration rate, albuminuria, glomerular and tubulointerstitial injury, inflammation) and cardiac injury (cardiac fibrosis, heart weight, gene expression) between C3aR knockout and wildtype mice as well as C3aR/C5aR1 double knockout respectively. Ang II as well as DOCA salt induced hypertension resulted in an increased number of Tregs in the kidney. Isolation of a very pure (&gt;99%) Treg population from a RORC x FIR double fluorescence reporter mouse revealed low abundance of C3aR and absence of C5aR1 in murine Tregs. Conclusions: In summary, hypertensive nephropathy in patients and mice is characterized by an increased expression of anaphylatoxin receptors and Tregs. However, deficiency of C3aR alone or C3aR and C5aR1 combined does not influence blood pressure or hypertensive end organ damage. Targeting the anaphylatoxin receptors C3aR alone or in combination with C5aR1 is not useful to treat cardiovascular disease in hypertension.

Honokiol suppresses the aberrant interactions between renal resident macrophages and tubular epithelial cells in lupus nephritis through the NLRP3/IL-33/ST2 axis

Lupus nephritis (LN) is a type of immune-complex nephritis caused by systemic lupus erythematosus and is a major contributor to mortality and morbidity. Honokiol (HNK) has been found to have a therapeutic effect on LN, but its action mechanism remains unclear. In this study, we first demonstrated that HNK attenuates kidney injury in MRL/lpr mice. Results from RNA sequencing combined with ingenuity pathway analysis suggested that HNK plays an anti-LN role through inhibition of the NLRP3 inflammasome and IL33. GEO chip data, single-cell data, and clinical samples from LN patients demonstrated that the pyroptosis and IL-33/ST2 pathways are abnormally activated during the stage of LN. In vivo, similar to the results of the AAV-mediated NLRP3 shRNA MRL/lpr model, HNK downregulated serum and renal IL-33 levels, and suppressed NLRP3 inflammasome and the IL-33/ST2 axis in the kidney. In vitro, co-culturing NLRP3-overexpressing or IL-33 knocked-down rat renal macrophages with NRK-52E cells confirmed that NLRP3 activation in resident macrophages directly upregulates IL-33, which in turn mediates the IL-33/ST2/NF-κB pathway to promote the inflammatory response of renal tubular epithelial cells. Furthermore, a molecular docking model and surface plasmon resonance analysis were utilized to demonstrate a direct interaction between HNK and NLRP3. In conclusion, this study provides a novel anti-LN treatment strategy in which HNK plays a preventive and therapeutic role against LN by suppressing the abnormal crosstalk between renal resident macrophages and renal tubular epithelial cells by inhibiting the activation of the NLRP3/IL-33/ST2 axis.

The Mechanism of Hyperglycemia-Induced Renal Cell Injury in Diabetic Nephropathy Disease: An Update.

Diabetic Nephropathy (DN) is a serious complication of type I and II diabetes. It develops from the initial microproteinuria to end-stage renal failure. The main initiator for DN is chronic hyperglycemia. Hyperglycemia (HG) can stimulate the resident and non-resident renal cells to produce humoral mediators and cytokines that can lead to functional and phenotypic changes in renal cells and tissues, interference with cell growth, interacting proteins, advanced glycation end products (AGEs), etc., ultimately resulting in glomerular and tubular damage and the onset of kidney disease. Therefore, poor blood glucose control is a particularly important risk factor for the development of DN. In this paper, the types and mechanisms of DN cell damage are classified and summarized by reviewing the related literature concerning the effect of hyperglycemia on the development of DN. At the cellular level, we summarize the mechanisms and effects of renal damage by hyperglycemia. This is expected to provide therapeutic ideas and inspiration for further studies on the treatment of patients with DN.

Recent advances in molecular mechanisms of acute kidney injury in patients with diabetes mellitus.

Several insults can lead to acute kidney injury (AKI) in native kidney and transplant patients, with diabetes critically contributing as pivotal risk factor. High glucose per se can disrupt several signaling pathways within the kidney that, if not restored, can favor the instauration of mechanisms of maladaptive repair, altering kidney homeostasis and proper function. Diabetic kidneys frequently show reduced oxygenation, vascular damage and enhanced inflammatory response, features that increase the kidney vulnerability to hypoxia. Importantly, epidemiologic data shows that previous episodes of AKI increase susceptibility to diabetic kidney disease (DKD), and that patients with DKD and history of AKI have a generally worse prognosis compared to DKD patients without AKI; it is therefore crucial to monitor diabetic patients for AKI. In the present review, we will describe the causes that contribute to increased susceptibility to AKI in diabetes, with focus on the molecular mechanisms that occur during hyperglycemia and how these mechanisms expose the different types of resident renal cells to be more vulnerable to maladaptive repair during AKI (contrast- and drug-induced AKI). Finally, we will review the list of the existing candidate biomarkers of diagnosis and prognosis of AKI in patients with diabetes.

Nephropathy Is Aggravated by Fatty Acids in Diabetic Kidney Disease through Tubular Epithelial Cell Necroptosis and Is Alleviated by an RIPK-1 Inhibitor

Introduction: Diabetic kidney disease (DKD), one of the leading causes of end-stage renal disease, has complex pathogenic mechanisms and few effective clinical therapies. DKD progression is accompanied by the loss of renal resident cells, followed by chronic inflammation and extracellular matrix deposition. Necroptosis is a newly discovered form of regulated cell death and is a major form of intrinsic cell loss in certain diabetic complications such as cardiomyopathy, intestinal disease, and retinal neuropathy; however, its significance in DKD is largely unknown. Methods: In this study, the expression of necroptosis marker phosphorylated MLKL (p-MLKL) in renal biopsy tissues of patients with DKD was detected using immunofluorescence and semiquantified using immunohistochemistry. The effects of different disease-causing factors on necroptosis activation in human HK-2 cells were evaluated using immunofluorescence and Western blotting. db/db diabetic mice were fed a high-fat diet to establish an animal model of DKD with significant renal tubule damage. Mice were treated with the RIPK1 inhibitor RIPA-56 to evaluate its renal protective effects. mRNA transcriptome sequencing was used to explore the changes in signaling pathways after RIPA-56 treatment. Oil red O staining and electron macroscopy were used to observe lipid droplet accumulation in renal biopsy tissues and mouse kidney tissues. Results: Immunostaining of phosphorylated RIPK1/RIPK3/MLKL verified the occurrence of necroptosis in renal tubular epithelial cells of patients with DKD. The level of the necroptosis marker p-MLKL correlated positively with the severity of renal functional, pathological damages, and lipid droplet accumulation in patients with DKD. High glucose and fatty acids were the main factors causing necroptosis in human renal tubular HK-2 cells. Renal function deterioration and renal pathological injury were accelerated, and the necroptosis pathway was activated in db/db mice fed a high-fat diet. Application of RIPA-56 effectively reduced the degree of renal injury, inhibited the necroptosis pathway activation, and reduced necroinflammation and lipid droplet accumulation in the renal tissues of db/db mice fed a high-fat diet. Conclusion: The present study revealed the role of necroptosis in the progression of DKD and might provide a new therapeutic target for the treatment of DKD.

A Clinical Approach of Lupus Nephritis Associated with Catastrophic Antiphospholipid - Antibody Syndrome - Review and Case Report

Abstract Glomerulonephritis is a major cause of morbidity in systemic lupus erythematosus (SLE). In fact, immune complex formation and deposition in the kidney results in intraglomerular inflammation with recruitment of leukocytes and activation and proliferation of resident renal cells. Intense injury may destroy resident renal cells by necrosis or apoptosis resulting in fibrinoid necrosis. When injury is less intense, endocapillary cells respond by proliferating and production of extracellular matrix (proliferative lesions). Renal biopsy, examination of urine sediment and measurement of C3 levels (and to less anti-DNA titers) are essential for the management of lupus nephritis. Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by thrombotic episodes in the arterial or venous circulation, in the presence of antiphospholipid antibodies (aPL), namely lupus anticoagulant (LA), anticardiolipin antibodies, and anti-β2glycoprotein-I antibodies (anti-β2GPI). Catastrophic APS (CAPS) is a very rare (---lt---1%) and extremely severe variant of APS. It is characterized by multiple systems and thrombotic organ involvement that occurs in a very short period (days to weeks). Renal involvement is a common feature in CAPS, the most frequent finding is thrombotic microangiopathy (TMA), but other chronic lesions of APSN can also be found.

Gender and Renal Insufficiency: Opportunities for Their Therapeutic Management?

Acute kidney injury (AKI) is a major clinical problem associated with increased morbidity and mortality. Despite intensive research, the clinical outcome remains poor, and apart from supportive therapy, no other specific therapy exists. Furthermore, acute kidney injury increases the risk of developing chronic kidney disease (CKD) and end-stage renal disease. Acute tubular injury accounts for the most common intrinsic cause of AKI. The main site of injury is the proximal tubule due to its high workload and energy demand. Upon injury, an intratubular subpopulation of proximal epithelial cells proliferates and restores the tubular integrity. Nevertheless, despite its strong regenerative capacity, the kidney does not always achieve its former integrity and function and incomplete recovery leads to persistent and progressive CKD. Clinical and experimental data demonstrate sexual differences in renal anatomy, physiology, and susceptibility to renal diseases including but not limited to ischemia-reperfusion injury. Some data suggest the protective role of female sex hormones, whereas others highlight the detrimental effect of male hormones in renal ischemia-reperfusion injury. Although the important role of sex hormones is evident, the exact underlying mechanisms remain to be elucidated. This review focuses on collecting the current knowledge about sexual dimorphism in renal injury and opportunities for therapeutic manipulation, with a focus on resident renal progenitor stem cells as potential novel therapeutic strategies.

Elevated expression of receptors for EGF, PDGF, transferrin and folate within murine and human lupus nephritis kidneys

ObjectiveSystemic lupus erythematosus (SLE) is a chronic autoimmune disease where the body's immune system targets cells and tissue in numerous organs, including the kidneys. Lupus nephritis (LN) is a highly heterogeneous disease, and diagnosis is difficult because clinical manifestations vary widely among patients. Comprehensive proteomic studies reported recently in LN have identified several urinary proteins which are also cell-surface receptors. If indeed these receptor proteins are also hyper-expressed within the kidneys, ligands to these receptors may be useful for drug targeting. MethodsscRNA sequence data analysis and immunohistochemistry were performed on LN kidneys for expression of four implicated receptors, EGFR, FOL2R2, PDGF-RB, and TFRC. ResultsIn reported scRNA sequencing studies from 21 LN patients and 3 healthy control renal biopsies or renal-infiltrating immune cells from 24 LN biopsies, EGFR, FOLR2, PDGF-Rb, and TFRC were all hyper expressed within LN kidneys in comparison to healthy kidneys, either within resident renal cells or infiltrating leukocytes. Immunohistochemistry staining of murine lupus renal biopsies from lupus mice revealed EGFR, FOLR2, TFRC and PDGF-RB were elevated in LN kidneys. Immunohistochemistry staining of human Class II, Class III, and Class IV kidney tissue sections revealed EGFR, TFRC, and PDGF-RB were significantly elevated in proliferative LN kidneys. ConclusionThese findings underscore the potential of EGFR, TFRC, FOLR2, and PDGF-RB as promising receptors for potential drug-targeting in LN.

Resident Renal Dendritic Cells Respond to Salt-Sensitive Hypertension via ToneBP, Leading to Increased Interleukin 6

Resident Renal Dendritic Cells Respond to Salt-Sensitive Hypertension via ToneBP, Leading to Increased Interleukin 6

A Clinical Approach of Lupus Nephritis Associated with Catastrophic Antiphospholipid-Antibody Syndrome Review and Case Report

Glomerulonephritis is a major cause of morbidity in systemic lupus erythematosus (SLE). In fact, immune complex formation and deposition in the kidney results in intraglomerular inflammation with recruitment of leukocytes, and activation and proliferation of resident renal cells. Intense injury may destroy resident renal cells by necrosis or apoptosis resulting in fibrinoid necrosis. When injury is less intense, endocapillary cells respond by proliferating and production of extracellular matrix (proliferative lesions). Renal biopsy, examination of urine sediment and measurement of C3 levels (and to less anti-DNA titers) are essential for the management of lupus nephritis. Treatment depends on the severity of the lupus nephritis. Disease severity depends on the presence or absence of high-risk factors. These include demographic (male gender, black race), clinical (failure to achieve response or marked delay in response, multiple relapses, pregnancy), laboratory (impaired renal function, severe anemia with hematocrit less than 26%) and histologic features (mixed membrane- proliferative or proliferative nephritis; cellular crescents and/or fibrinoid necrosis; cellular crescent and/or fibrinoid necrosis; and moderate to high degrees of interstitial fibrosis and/or tubular atrophy).

Update on Innate Immunity in Acute Kidney Injury-Lessons Taken from COVID-19.

The serious clinical course of SARS-CoV-2 infection is usually accompanied by acute kidney injury (AKI), worsening prognosis and increasing mortality. AKI in COVID-19 is above all a consequence of systemic dysregulations leading to inflammation, thrombosis, vascular endothelial damage and necrosis. All these processes rely on the interactions between innate immunity elements, including circulating blood cells, resident renal cells, their cytokine products, complement systems, coagulation cascades and contact systems. Numerous simultaneous pathways of innate immunity should secure an effective host defense. Since they all form a network of cross-linked auto-amplification loops, uncontrolled activation is possible. When the actions of selected pathways amplify, cascade activation evades control and the propagation of inflammation and necrosis worsens, accompanied by complement overactivity and immunothrombosis. The systemic activation of innate immunity reaches the kidney, where the damage affecting single tubular cells spreads through tissue collateral damage and triggers AKI. This review is an attempt to synthetize the connections between innate immunity components engaged in COVID-19-related AKI and to summarize the knowledge on the pathophysiological background of processes responsible for renal damage.