scholarly journals CD40/CD40L Signaling as a Promising Therapeutic Target for the Treatment of Renal Disease

2020 ◽  
Vol 9 (11) ◽  
pp. 3653
Author(s):  
Shungang Zhang ◽  
Joshua D. Breidenbach ◽  
Benjamin H. Russell ◽  
Jerrin George ◽  
Steven T. Haller
Keyword(s):  
Kidney Disease ◽  
Kidney Injury ◽  
Cell Types ◽  
Cd40 Ligand ◽  
Kidney Cells ◽  
Immune Functions ◽  
Promising Therapeutic Target ◽  
Signaling Axis ◽  
Soluble Cd40l ◽  
Cluster Of Differentiation

The cluster of differentiation 40 (CD40) is activated by the CD40 ligand (CD40L) in a variety of diverse cells types and regulates important processes associated with kidney disease. The CD40/CD40L signaling cascade has been comprehensively studied for its roles in immune functions, whereas the signaling axis involved in local kidney injury has only drawn attention in recent years. Clinical studies have revealed that circulating levels of soluble CD40L (sCD40L) are associated with renal function in the setting of kidney disease. Levels of the circulating CD40 receptor (sCD40), sCD40L, and local CD40 expression are tightly related to renal injury in different types of kidney disease. Additionally, various kidney cell types have been identified as non-professional antigen-presenting cells (APCs) that express CD40 on the cell membrane, which contributes to the interactions between immune cells and local kidney cells during the development of kidney injury. Although the potential for adverse CD40 signaling in kidney cells has been reported in several studies, a summary of those studies focusing on the role of CD40 signaling in the development of kidney disease is lacking. In this review, we describe the outcomes of recent studies and summarize the potential therapeutic methods for kidney disease which target CD40.

scholarly journals Multi-Target Drugs for Kidney Diseases

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0003582021
Author(s):  
John D. Imig ◽  
Daniel Merk ◽  
Eugen Proschak
Keyword(s):  
Kidney Disease ◽  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Metabolic Diseases ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Glomerular Nephritis ◽  
Cell Signaling Pathways

Kidney diseases such as acute kidney injury (AKI), chronic kidney disease (CKD), and glomerular nephritis can lead to dialysis and the need for kidney transplantation. The pathologies for kidney diseases are extremely complex, progress at different rates, and involve several cell types and cell-signaling pathways. Complex kidney diseases require therapeutics that can act on multiple targets. In the past ten years, in silico design of drugs has allowed for multi-target drugs to go quickly from concept to reality. Several multi-target drugs have been successfully made that target arachidonic acid pathways and transcription factors to treat inflammatory, fibrotic, and metabolic diseases. Multi-target drugs have also demonstrated great potential to treat diabetic nephropathy and fibrotic kidney disease. These drugs act by decreasing renal transforming growth factor-β (TGF-β) signaling, inflammation, mitochondrial dysfunction, and oxidative stress. There are several other recently developed multi-target drugs that have yet to be tested for their ability to combat kidney diseases. Overall, there is excellent potential for multi-target drugs that act on several cell types and signaling pathways to treat kidney diseases.

scholarly journals Coronavirus Disease (COVID)-19 and Diabetic Kidney Disease

2021 ◽  
Vol 14 (8) ◽  
pp. 751
Author(s):  
Swayam Prakash Srivastava ◽  
Rohit Srivastava ◽  
Subhash Chand ◽  
Julie E. Goodwin
Keyword(s):  
Kidney Disease ◽  
Viral Entry ◽  
Diabetic Kidney Disease ◽  
Thrombus Formation ◽  
Renin Angiotensin System ◽  
Cell Types ◽  
Protective Role ◽  
Kidney Cells ◽  
Diabetic Kidney

The present review describes COVID-19 severity in diabetes and diabetic kidney disease. We discuss the crucial effect of COVID-19-associated cytokine storm and linked injuries and associated severe mesenchymal activation in tubular epithelial cells, endothelial cells, and macrophages that influence neighboring cell homeostasis, resulting in severe proteinuria and organ fibrosis in diabetes. Altered microRNA expression disrupts cellular homeostasis and the renin-angiotensin-system, targets reno-protective signaling proteins, such as angiotensin-converting enzyme 2 (ACE2) and MAS1 receptor (MAS), and facilitates viral entry and replication in kidney cells. COVID-19-associated endotheliopathy that interacts with other cell types, such as neutrophils, platelets, and macrophages, is one factor that accelerates prethrombotic reactions and thrombus formation, resulting in organ failures in diabetes. Apart from targeting vital signaling through ACE2 and MAS, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are also associated with higher profibrotic dipeptidyl transferase-4 (DPP-4)-mediated mechanisms and suppression of AMP-activated protein kinase (AMPK) activation in kidney cells. Lowered DPP-4 levels and restoration of AMPK levels are organ-protective, suggesting a pathogenic role of DPP-4 and a protective role of AMPK in diabetic COVID-19 patients. In addition to standard care provided to COVID-19 patients, we urgently need novel drug therapies that support the stability and function of both organs and cell types in diabetes.

scholarly journals Kidney Single-Cell Atlas Reveals Myeloid Heterogeneity in Progression and Regression of Kidney Disease

2020 ◽  
Vol 31 (12) ◽  
pp. 2833-2854
Author(s):  
Bryan R. Conway ◽  
Eoin D. O’Sullivan ◽  
Carolynn Cairns ◽  
James O’Sullivan ◽  
Daniel J. Simpson ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Kidney Disease ◽  
Single Cell ◽  
Single Cells ◽  
Kidney Injury ◽  
Myeloid Cell ◽  
Cell Types ◽  
Blood Exchange ◽  
Transcriptomic Level ◽  
Injury And Repair

BackgroundLittle is known about the roles of myeloid cell subsets in kidney injury and in the limited ability of the organ to repair itself. Characterizing these cells based only on surface markers using flow cytometry might not provide a full phenotypic picture. Defining these cells at the single-cell, transcriptomic level could reveal myeloid heterogeneity in the progression and regression of kidney disease.MethodsIntegrated droplet– and plate-based single-cell RNA sequencing were used in the murine, reversible, unilateral ureteric obstruction model to dissect the transcriptomic landscape at the single-cell level during renal injury and the resolution of fibrosis. Paired blood exchange tracked the fate of monocytes recruited to the injured kidney.ResultsA single-cell atlas of the kidney generated using transcriptomics revealed marked changes in the proportion and gene expression of renal cell types during injury and repair. Conventional flow cytometry markers would not have identified the 12 myeloid cell subsets. Monocytes recruited to the kidney early after injury rapidly adopt a proinflammatory, profibrotic phenotype that expresses Arg1, before transitioning to become Ccr2+ macrophages that accumulate in late injury. Conversely, a novel Mmp12+ macrophage subset acts during repair.ConclusionsComplementary technologies identified novel myeloid subtypes, based on transcriptomics in single cells, that represent therapeutic targets to inhibit progression or promote regression of kidney disease.

scholarly journals Cell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Michael Lacy ◽  
Christina Bürger ◽  
Annelie Shami ◽  
Maiwand Ahmadsei ◽  
Holger Winkels ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Types ◽  
Cd40 Ligand ◽  
Interferon Γ ◽  
Therapeutic Strategies ◽  
Atherosclerotic Plaques ◽  
Atherosclerotic Vascular Disease ◽  
Multiple Functions ◽  
Signaling Axis ◽  
Th1 Polarization

AbstractAtherosclerosis is a major underlying cause of cardiovascular disease. Previous studies showed that inhibition of the co-stimulatory CD40 ligand (CD40L)-CD40 signaling axis profoundly attenuates atherosclerosis. As CD40L exerts multiple functions depending on the cell-cell interactions involved, we sought to investigate the function of the most relevant CD40L-expressing cell types in atherosclerosis: T cells and platelets. Atherosclerosis-prone mice with a CD40L-deficiency in CD4+ T cells display impaired Th1 polarization, as reflected by reduced interferon-γ production, and smaller atherosclerotic plaques containing fewer T-cells, smaller necrotic cores, an increased number of smooth muscle cells and thicker fibrous caps. Mice with a corresponding CD40-deficiency in CD11c+ dendritic cells phenocopy these findings, suggesting that the T cell-dendritic cell CD40L-CD40 axis is crucial in atherogenesis. Accordingly, sCD40L/sCD40 and interferon-γ concentrations in carotid plaques and plasma are positively correlated in patients with cerebrovascular disease. Platelet-specific deficiency of CD40L does not affect atherogenesis but ameliorates atherothrombosis. Our results establish divergent and cell-specific roles of CD40L-CD40 in atherosclerosis, which has implications for therapeutic strategies targeting this pathway.

scholarly journals An atlas of healthy and injured cell states and niches in the human kidney

2021 ◽  
Author(s):  
Blue B. Lake ◽  
Rajasree Menon ◽  
Seth Winfree ◽  
Qiwen Hu ◽  
Ricardo Melo Ferreira ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Immune Responses ◽  
Large Scale ◽  
3D Imaging ◽  
Kidney Injury ◽  
Human Kidney ◽  
Cell Types ◽  
Molecular Signatures ◽  
Imaging Analysis ◽  
Future Studies

Understanding kidney disease relies upon defining the complexity of cell types and states, their associated molecular profiles, and interactions within tissue neighborhoods. We have applied multiple single-cell or -nucleus assays (>400,000 nuclei/cells) and spatial imaging technologies to a broad spectrum of healthy reference (n = 42) and disease (n = 42) kidneys. This has provided a high resolution cellular atlas of 100 cell types that include rare and novel cell populations. The multi-omic approach provides detailed transcriptomic profiles, epigenomic regulatory factors, and spatial localizations for major cell types spanning the entire kidney. We further identify and define cellular states altered in kidney injury, encompassing cycling, adaptive or maladaptive repair, transitioning and degenerative states affecting several segments. Molecular signatures of these states permitted their localization within injury neighborhoods using spatial transcriptomics, and large-scale 3D imaging analysis of ~1.2 million neighborhoods provided linkages to active immune responses. These analyses further defined biological pathways relevant to injury niches, including signatures underlying the transition from reference to predicted maladaptive states that were associated with a decline in kidney function during chronic kidney disease. This human kidney cell atlas, including injury cell states and neighborhoods, will be a valuable resource for future studies.

scholarly journals Inflammation and Kidney Injury in Diabetic African American Men

2019 ◽  
Vol 2019 ◽  
pp. 1-12
Author(s):  
Lei Cao ◽  
Ava Boston ◽  
Olugbemiga Jegede ◽  
Heather A. Newman ◽  
Scott H. Harrison ◽  
...  
Keyword(s):  
African American ◽  
Kidney Disease ◽  
Molecular Mechanisms ◽  
African American Men ◽  
Kidney Injury ◽  
Diabetic Patients ◽  
Tnf Receptor ◽  
Urinary Levels ◽  
Signaling Axis ◽  
Multiple Biomarkers

African Americans are disproportionately burdened by diabetic kidney disease (DKD). However, little is known about the cellular and molecular mechanisms underlying the onset and progression of DKD in this population. The goal of the current study was to determine the association between specific inflammation markers and kidney injury in diabetic African American men. To this end, we recruited diabetic patients either with (n=20) or without (n=87) diagnosed kidney disease along with age-matched nondiabetic controls (n=81). Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFR) were used for biochemical assessment of kidney function. We then measured plasma and urinary levels of seven inflammatory markers, including adiponectin, C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), TNF receptor 1 (TNFR1), TNF receptor 2 (TNFR2), interleukin-6 (IL-6), and intercellular cell adhesion molecule-1 (ICAM-1). Plasma levels of TNF-α, TNFR1, and TNFR2 were significantly higher in diabetics with macroalbuminuria compared to nondiabetic controls and diabetics with normoalbuminuria or microalbuminuria. Likewise, urinary levels of ICAM-1 were higher in diabetics with macroalbuminuria compared to the other groups. Indeed, urinary ICAM-1, plasma TNF-α, and adiponectin had moderate positive correlations with UACR while plasma TNFR1 and TNFR2 levels were strongly correlated with kidney injury, indicated by multiple biomarkers of kidney injury. In contrast, though plasma CRP was elevated in diabetic subjects relative to nondiabetic controls, its levels did not correlate with kidney injury. Together, these data suggest that inflammation, particularly that mediated by the TNF-α/NF-κB signaling axis, may play a role in the pathogenesis of DKD in African American men.

scholarly journals Role of TRPA1 in Tissue Damage and Kidney Disease

2021 ◽  
Vol 22 (7) ◽  
pp. 3415
Author(s):  
Chung-Kuan Wu ◽  
Ji-Fan Lin ◽  
Tzong-Shyuan Lee ◽  
Yu Ru Kou ◽  
Der-Cherng Tarng
Keyword(s):  
Kidney Disease ◽  
Tissue Damage ◽  
Animal Studies ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Cell Types ◽  
Renal Tubular

TRPA1, a nonselective cation channel, is expressed in sensory afferent that innervates peripheral targets. Neuronal TRPA1 can promote tissue repair, remove harmful stimuli and induce protective responses via the release of neuropeptides after the activation of the channel by chemical, exogenous, or endogenous irritants in the injured tissue. However, chronic inflammation after repeated noxious stimuli may result in the development of several diseases. In addition to sensory neurons, TRPA1, activated by inflammatory agents from some non-neuronal cells in the injured area or disease, might promote or protect disease progression. Therefore, TRPA1 works as a molecular sentinel of tissue damage or as an inflammation gatekeeper. Most kidney damage cases are associated with inflammation. In this review, we summarised the role of TRPA1 in neurogenic or non-neurogenic inflammation and in kidney disease, especially the non-neuronal TRPA1. In in vivo animal studies, TRPA1 prevented sepsis-induced or Ang-II-induced and ischemia-reperfusion renal injury by maintaining mitochondrial haemostasis or via the downregulation of macrophage-mediated inflammation, respectively. Renal tubular epithelial TRPA1 acts as an oxidative stress sensor to mediate hypoxia–reoxygenation injury in vitro and ischaemia–reperfusion-induced kidney injury in vivo through MAPKs/NF-kB signalling. Acute kidney injury (AKI) patients with high renal tubular TRPA1 expression had low complete renal function recovery. In renal disease, TPRA1 plays different roles in different cell types accordingly. These findings depict the important role of TRPA1 and warrant further investigation.

scholarly journals Molecular Mechanisms of Kidney Injury and Repair in Arterial Hypertension

2019 ◽  
Vol 20 (9) ◽  
pp. 2138 ◽  
Author(s):  
Laura Katharina Sievers ◽  
Kai-Uwe Eckardt
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Arterial Hypertension ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Kidney Injury ◽  
Cell Types ◽  
Molecular Signaling ◽  
Systemic Signaling ◽  
Injury And Repair

The global burden of chronic kidney disease is rising. The etiologies, heterogeneous, and arterial hypertension, are key factors contributing to the development and progression of chronic kidney disease. Arterial hypertension is induced and maintained by a complex network of systemic signaling pathways, such as the hormonal axis of the renin-angiotensin-aldosterone system, hemodynamic alterations affecting blood flow, oxygen supply, and the immune system. This review summarizes the clinical and histopathological features of hypertensive kidney injury and focusses on the interplay of distinct systemic signaling pathways, which drive hypertensive kidney injury in distinct cell types of the kidney. There are several parallels between hypertension-induced molecular signaling cascades in the renal epithelial, endothelial, interstitial, and immune cells. Angiotensin II signaling via the AT1R, hypoxia induced HIFα activation and mechanotransduction are closely interacting and further triggering the adaptions of metabolism, cytoskeletal rearrangement, and profibrotic TGF signaling. The interplay of these, and other cellular pathways, is crucial to balancing the injury and repair of the kidneys and determines the progression of hypertensive kidney disease.

Renal C3 Production Drives Acute Kidney Injury and Acute Kidney Disease in Diabetics with Sepsis

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1737-P
Author(s):  
LYNN M. FRYDRYCH ◽  
GUOWU BIAN ◽  
PETER A. WARD ◽  
MARKUS BITZER ◽  
MATTHEW DELANO
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Kidney Injury ◽  
Acute Kidney Disease
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