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 Albumin contributes to kidney disease progression in Alport syndrome

2016 ◽  
Vol 311 (1) ◽  
pp. F120-F130 ◽  
Author(s):  
George Jarad ◽  
Russell H. Knutsen ◽  
Robert P. Mecham ◽  
Jeffrey H. Miner
Keyword(s):  
Kidney Disease ◽  
Basement Membrane ◽  
Glomerular Basement Membrane ◽  
Alport Syndrome ◽  
Transforming Growth Factor ◽  
Kidney Diseases ◽  
Serum Triglyceride ◽  
Transforming Growth Factor Β ◽  
Collagen Type Iv ◽  
Albumin Concentration

Alport syndrome is a familial kidney disease caused by defects in the collagen type IV network of the glomerular basement membrane. Lack of collagen-α3α4α5(IV) changes the glomerular basement membrane morphologically and functionally, rendering it leaky to albumin and other plasma proteins. Filtered albumin has been suggested to be a cause of the glomerular and tubular injuries observed at advanced stages of Alport syndrome. To directly investigate the role that albumin plays in the progression of disease in Alport syndrome, we generated albumin knockout ( Alb−/−) mice to use as a tool for removing albuminuria as a component of kidney disease. Mice lacking albumin were healthy and indistinguishable from control littermates, although they developed hypertriglyceridemia. Dyslipidemia was observed in Alb+/− mice, which displayed half the normal plasma albumin concentration. Alb mutant mice were bred to collagen-α3(IV) knockout ( Col4a3−/−) mice, which are a model for human Alport syndrome. Lack of circulating and filtered albumin in Col4a3−/−; Alb−/− mice resulted in dramatically improved kidney disease outcomes, as these mice lived 64% longer than did Col4a3−/−; Alb+/+ and Col4a3−/−; Alb+/− mice, despite similar blood pressures and serum triglyceride levels. Further investigations showed that the absence of albumin correlated with reduced transforming growth factor-β1 signaling as well as reduced tubulointerstitial, glomerular, and podocyte pathology. We conclude that filtered albumin is injurious to kidney cells in Alport syndrome and perhaps in other proteinuric kidney diseases, including diabetic nephropathy.

Increased tubulointerstitial recruitment of human CD141hi CLEC9A+ and CD1c+ myeloid dendritic cell subsets in renal fibrosis and chronic kidney disease

2013 ◽  
Vol 305 (10) ◽  
pp. F1391-F1401 ◽  
Author(s):  
Andrew J. Kassianos ◽  
Xiangju Wang ◽  
Sandeep Sampangi ◽  
Kimberly Muczynski ◽  
Helen Healy ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Kidney Diseases ◽  
Kidney Tissue ◽  
Transforming Growth Factor Β ◽  
Healthy Tissue ◽  
Lectin Domain ◽  
Immune Mediated

Dendritic cells (DCs) play critical roles in immune-mediated kidney diseases. Little is known, however, about DC subsets in human chronic kidney disease, with previous studies restricted to a limited set of pathologies and to using immunohistochemical methods. In this study, we developed novel protocols for extracting renal DC subsets from diseased human kidneys and identified, enumerated, and phenotyped them by multicolor flow cytometry. We detected significantly greater numbers of total DCs as well as CD141hi and CD1c+ myeloid DC (mDCs) subsets in diseased biopsies with interstitial fibrosis than diseased biopsies without fibrosis or healthy kidney tissue. In contrast, plasmacytoid DC numbers were significantly higher in the fibrotic group compared with healthy tissue only. Numbers of all DC subsets correlated with loss of kidney function, recorded as estimated glomerular filtration rate. CD141hi DCs expressed C-type lectin domain family 9 member A (CLEC9A), whereas the majority of CD1c+ DCs lacked the expression of CD1a and DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN), suggesting these mDC subsets may be circulating CD141hi and CD1c+ blood DCs infiltrating kidney tissue. Our analysis revealed CLEC9A+ and CD1c+ cells were restricted to the tubulointerstitium. Notably, DC expression of the costimulatory and maturation molecule CD86 was significantly increased in both diseased cohorts compared with healthy tissue. Transforming growth factor-β levels in dissociated tissue supernatants were significantly elevated in diseased biopsies with fibrosis compared with nonfibrotic biopsies, with mDCs identified as a major source of this profibrotic cytokine. Collectively, our data indicate that activated mDC subsets, likely recruited into the tubulointerstitium, are positioned to play a role in the development of fibrosis and, thus, progression to chronic kidney disease.

scholarly journals Stimulation of lymphocyte responses by angiotensin II promotes kidney injury in hypertension

2008 ◽  
Vol 295 (2) ◽  
pp. F515-F524 ◽  
Author(s):  
Steven D. Crowley ◽  
Campbell W. Frey ◽  
Samantha K. Gould ◽  
Robert Griffiths ◽  
Phillip Ruiz ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Cardiac Hypertrophy ◽  
Transforming Growth Factor ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Transforming Growth Factor Β ◽  
Ang Ii ◽  
Lymphocyte Responses ◽  
Stimulation Of

Activation of the renin-angiotensin system contributes to the progression of chronic kidney disease. Based on the known cellular effects of ANG II to promote inflammation, we posited that stimulation of lymphocyte responses by ANG II might contribute to the pathogenesis of hypertensive kidney injury. We therefore examined the effects of the immunosuppressive agent mycophenolate mofetil (MMF) on the course of hypertension and kidney disease induced by chronic infusion of ANG II in 129/SvEv mice. Although it had no effect on the severity of hypertension or cardiac hypertrophy, treatment with MMF significantly reduced albuminuria and ameliorated kidney injury, decreasing glomerulosclerosis and reducing lymphocyte infiltration into the renal interstitium. Attenuation of renal pathology with MMF was associated with reduced expression of mRNAs for the proinflammatory cytokines interferon-γ and tumor necrosis factor-α and the profibrotic cytokine transforming growth factor-β. As infiltration of the kidney by T lymphocytes was a prominent feature of ANG II-dependent renal injury, we carried out experiments examining the effects of ANG II on lymphocytes in vitro. We find that exposure of splenic lymphocytes to ANG II causes prominent rearrangements of the actin cytoskeleton. These actions require the activity of Rho kinase. Thus, ANG II exaggerates hypertensive kidney injury by stimulating lymphocyte responses. These proinflammatory actions of ANG II seem to have a proclivity for inducing kidney injury while having negligible actions in the pathogenesis of cardiac hypertrophy.

scholarly journals A perspective on chronic kidney disease progression

2017 ◽  
Vol 312 (3) ◽  
pp. F375-F384 ◽  
Author(s):  
Jianyong Zhong ◽  
Hai-Chun Yang ◽  
Agnes B. Fogo
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Transforming Growth Factor ◽  
Kidney Injury ◽  
Transforming Growth Factor Β ◽  
New Drugs ◽  
Kidney Disease Progression ◽  
Kidney Injury Molecule 1 ◽  
End Stage ◽  
Neutrophil Gelatinase

Chronic kidney disease (CKD) will progress to end stage without treatment, but the decline of renal function may not be linear. Compared with glomerular filtration rate and proteinuria, new surrogate markers, such as kidney injury molecule-1, neutrophil gelatinase-associated protein, apolipoprotein A-IV, and soluble urokinase receptor, may allow potential intervention and treatment in the earlier stages of CKD, which could be useful for clinical trials. New omic-based technologies reveal potential new genomic and epigenomic mechanisms that appear different from those causing the initial disease. Various clinical studies also suggest that acute kidney injury is a major risk for progressive CKD. To ameliorate the progression of CKD, the first step is optimizing renin-angiotensin-aldosterone system blockade. New drugs targeting endothelin, transforming growth factor-β, oxidative stress, and inflammatory- and cell-based regenerative therapy may have add-on benefit.

scholarly journals Senescence marker activin A is increased in human diabetic kidney disease: association with kidney function and potential implications for therapy

2019 ◽  
Vol 7 (1) ◽  
pp. e000720 ◽  
Author(s):  
Xiaohui Bian ◽  
Tomás P Griffin ◽  
Xiangyang Zhu ◽  
Md Nahidul Islam ◽  
Sabena M Conley ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Kidney Function ◽  
Diabetic Kidney Disease ◽  
Transforming Growth Factor ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Human Kidney ◽  
Activin A ◽  
Diabetic Kidney ◽  
Mesenchymal Transition

ObjectiveActivin A, an inflammatory mediator implicated in cellular senescence-induced adipose tissue dysfunction and profibrotic kidney injury, may become a new target for the treatment of diabetic kidney disease (DKD) and chronic kidney diseases. We tested the hypothesis that human DKD-related injury leads to upregulation of activin A in blood and urine and in a human kidney cell model. We further hypothesized that circulating activin A parallels kidney injury markers in DKD.Research design and methodsIn two adult diabetes cohorts and controls (Minnesota, USA; Galway, Ireland), the relationships between plasma (or urine) activin A, estimated glomerular filtration rate (eGFR) and DKD injury biomarkers were tested with logistic regression and correlation coefficients. Activin A, inflammatory, epithelial-mesenchymal-transition (EMT) and senescence markers were assayed in human kidney (HK-2) cells incubated in high glucose plus transforming growth factor-β1 or albumin.ResultsPlasma activin A levels were elevated in diabetes (n=206) compared with controls (n=76; 418.1 vs 259.3 pg/mL; p<0.001) and correlated inversely with eGFR (rs=−0.61; p<0.001; diabetes). After eGFR adjustment, only albuminuria (OR 1.56, 95% CI 1.16 to 2.09) and tumor necrosis factor receptor-1 (OR 6.40, 95% CI 1.08 to 38.00) associated with the highest activin tertile. Albuminuria also related to urinary activin (rs=0.65; p<0.001). Following in vitro HK-2 injury, activin, inflammatory, EMT genes and supernatant activin levels were increased.ConclusionsCirculating activin A is increased in human DKD and correlates with reduced kidney function and kidney injury markers. DKD-injured human renal tubule cells develop a profibrotic and inflammatory phenotype with activin A upregulation. These findings underscore the role of inflammation and provide a basis for further exploration of activin A as a diagnostic marker and therapeutic target in DKD.

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.

scholarly journals Fibroblasts Influence the Efficacy, Resistance, and Future Use of Vaccines and Immunotherapy in Cancer Treatment

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 634
Author(s):  
Bailee H. Sliker ◽  
Paul M. Campbell
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Fibroblast Activation Protein ◽  
Cancer Associated Fibroblasts ◽  
Cell Type ◽  
Adaptive Immune ◽  
Adaptive Immune Cells ◽  
New Research ◽  
Tumor Types

Tumors are composed of not only epithelial cells but also many other cell types that contribute to the tumor microenvironment (TME). Within this space, cancer-associated fibroblasts (CAFs) are a prominent cell type, and these cells are connected to an increase in tumor progression as well as alteration of the immune landscape present in and around the tumor. This is accomplished in part by their ability to alter the presence of both innate and adaptive immune cells as well as the release of various chemokines and cytokines, together leading to a more immunosuppressive TME. Furthermore, new research implicates CAFs as players in immunotherapy response in many different tumor types, typically by blunting their efficacy. Fibroblast activation protein (FAP) and transforming growth factor β (TGF-β), two major CAF proteins, are associated with the outcome of different immunotherapies and, additionally, have become new targets themselves for immune-based strategies directed at CAFs. This review will focus on CAFs and how they alter the immune landscape within tumors, how this affects response to current immunotherapy treatments, and how immune-based treatments are currently being harnessed to target the CAF population itself.

scholarly journals CD73 Overexpression in Podocytes: A Novel Marker of Podocyte Injury in Human Kidney Disease

2021 ◽  
Vol 22 (14) ◽  
pp. 7642
Author(s):  
Zoran V. Popovic ◽  
Felix Bestvater ◽  
Damir Krunic ◽  
Bernhard K. Krämer ◽  
Raoul Bergner ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Membranous Glomerulonephritis ◽  
Human Kidney ◽  
Protective Role ◽  
Control Group ◽  
Podocyte Injury ◽  
Ccr2 Expression ◽  
Cd73 Expression

The CD73 pathway is an important anti-inflammatory mechanism in various disease settings. Observations in mouse models suggested that CD73 might have a protective role in kidney damage; however, no direct evidence of its role in human kidney disease has been described to date. Here, we hypothesized that podocyte injury in human kidney diseases alters CD73 expression that may facilitate the diagnosis of podocytopathies. We assessed the expression of CD73 and one of its functionally important targets, the C-C chemokine receptor type 2 (CCR2), in podocytes from kidney biopsies of 39 patients with podocytopathy (including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranous glomerulonephritis (MGN) and amyloidosis) and a control group. Podocyte CD73 expression in each of the disease groups was significantly increased in comparison to controls (p < 0.001–p < 0.0001). Moreover, there was a marked negative correlation between CD73 and CCR2 expression, as confirmed by immunohistochemistry and immunofluorescence (Pearson r = −0.5068, p = 0.0031; Pearson r = −0.4705, p = 0.0313, respectively), thus suggesting a protective role of CD73 in kidney injury. Finally, we identify CD73 as a novel potential diagnostic marker of human podocytopathies, particularly of MCD that has been notorious for the lack of pathological features recognizable by light microscopy and immunohistochemistry.

scholarly journals Expression and function of Smad7 in autoimmune and inflammatory diseases

2021 ◽  
Author(s):  
Yiping Hu ◽  
Juan He ◽  
Lianhua He ◽  
Bihua Xu ◽  
Qingwen Wang
Keyword(s):  
Posttranscriptional Regulation ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Kidney Diseases ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Signaling Mechanism ◽  
And Function

AbstractTransforming growth factor-β (TGF-β) plays a critical role in the pathological processes of various diseases. However, the signaling mechanism of TGF-β in the pathological response remains largely unclear. In this review, we discuss advances in research of Smad7, a member of the I-Smads family and a negative regulator of TGF-β signaling, and mainly review the expression and its function in diseases. Smad7 inhibits the activation of the NF-κB and TGF-β signaling pathways and plays a pivotal role in the prevention and treatment of various diseases. Specifically, Smad7 can not only attenuate growth inhibition, fibrosis, apoptosis, inflammation, and inflammatory T cell differentiation, but also promotes epithelial cells migration or disease development. In this review, we aim to summarize the various biological functions of Smad7 in autoimmune diseases, inflammatory diseases, cancers, and kidney diseases, focusing on the molecular mechanisms of the transcriptional and posttranscriptional regulation of Smad7.

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