scholarly journals The Updates of Podocyte Lipid Metabolism in Proteinuric Kidney Disease

2021 ◽  
pp. 1-14
Author(s):  
Yu Sun ◽  
Sijia Cui ◽  
Yunfeng Hou ◽  
Fan Yi
Keyword(s):  
Lipid Metabolism ◽  
Kidney Disease ◽  
Lipid Accumulation ◽  
Kidney Diseases ◽  
Early Event ◽  
Podocyte Injury ◽  
Mitochondrial Oxidative Stress ◽  
Filtration Barrier ◽  
Cytoskeleton Remodeling ◽  
And Function

<b><i>Background:</i></b> Podocytes, functionally specialized and terminally differentiated glomerular visceral epithelial cells, are critical for maintaining the structure and function of the glomerular filtration barrier. Podocyte injury is considered as the most important early event contributing to proteinuric kidney diseases such as obesity-related renal disease, diabetic kidney disease, focal segmental glomerulosclerosis, membranous nephropathy, and minimal change disease. Although considerable advances have been made in the understanding of mechanisms that trigger podocyte injury, cell-specific and effective treatments are not clinically available. <b><i>Summary:</i></b> Emerging evidence has indicated that the disorder of podocyte lipid metabolism is closely associated with various proteinuric kidney diseases. Excessive lipid accumulation in podocytes leads to cellular dysfunction which is defined as lipotoxicity, a phenomenon characterized by mitochondrial oxidative stress, actin cytoskeleton remodeling, insulin resistance, and inflammatory response that can eventually result in podocyte hypertrophy, detachment, and death. In this review, we summarize recent advances in the understanding of lipids in podocyte biological function and the regulatory mechanisms leading to podocyte lipid accumulation in proteinuric kidney disease. <b><i>Key Messages:</i></b> Targeting podocyte lipid metabolism may represent a novel therapeutic strategy for patients with proteinuric kidney disease.

scholarly journals Podocyte Lipotoxicity in CKD

Kidney360 ◽  
2021 ◽  
Vol 2 (4) ◽  
pp. 755-762
Author(s):  
Jin-Ju Kim ◽  
Sydney S. Wilbon ◽  
Alessia Fornoni
Keyword(s):  
Lipid Metabolism ◽  
Lipid Accumulation ◽  
Kidney Diseases ◽  
Treatment Options ◽  
The United States ◽  
Differentiated Cells ◽  
Filtration Barrier ◽  
And Function ◽  
Cellular Components ◽  
Novel Therapeutic

CKD represents the ninth most common cause of death in the United States but, despite this large health burden, treatment options for affected patients remain limited. To remedy this, several relevant pathways have been identified that may lead to novel therapeutic options. Among them, altered renal lipid metabolism, first described in 1982, has been recognized as a common pathway in clinical and experimental CKD of both metabolic and nonmetabolic origin. This observation has led many researchers to investigate the cause of this renal parenchyma lipid accumulation and its downstream effect on renal structure and function. Among key cellular components of the kidney parenchyma, podocytes are terminally differentiated cells that cannot be easily replaced when lost. Clinical and experimental evidence supports a role of reduced podocyte number in the progression of CKD. Given the importance of the podocytes in the maintenance of the glomerular filtration barrier and the accumulation of TG and cholesterol-rich lipid droplets in the podocyte and glomerulus in kidney diseases that cause CKD, understanding the upstream cause and downstream consequences of lipid accumulation in podocytes may lead to novel therapeutic opportunities. In this review, we hope to consolidate our understanding of the causes and consequences of dysregulated renal lipid metabolism in CKD development and progression, with a major focus on podocytes.

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 Beyond a Passive Conduit: Implications of Lymphatic Biology for Kidney Diseases

2020 ◽  
Vol 31 (6) ◽  
pp. 1178-1190 ◽  
Author(s):  
Daniyal J. Jafree ◽  
David A. Long
Keyword(s):  
Kidney Disease ◽  
Therapeutic Potential ◽  
Kidney Diseases ◽  
Transplant Rejection ◽  
Lymphatic Vessels ◽  
Renal Physiology ◽  
Clear Fluid ◽  
Adult Kidney ◽  
And Function ◽  
Development Structure

The kidney contains a network of lymphatic vessels that clear fluid, small molecules, and cells from the renal interstitium. Through modulating immune responses and via crosstalk with surrounding renal cells, lymphatic vessels have been implicated in the progression and maintenance of kidney disease. In this Review, we provide an overview of the development, structure, and function of lymphatic vessels in the healthy adult kidney. We then highlight the contributions of lymphatic vessels to multiple forms of renal pathology, emphasizing CKD, transplant rejection, and polycystic kidney disease and discuss strategies to target renal lymphatics using genetic and pharmacologic approaches. Overall, we argue the case for lymphatics playing a fundamental role in renal physiology and pathology and treatments modulating these vessels having therapeutic potential across the spectrum of kidney disease.

scholarly journals Recovery of kidney function in patients treated with maintenance dialysis—a report from the ERA-EDTA registry

2020 ◽  
Author(s):  
Lily Jakulj ◽  
Anneke Kramer ◽  
Anders Åsberg ◽  
Johan de Meester ◽  
Carmen Santiuste de Pablos ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Kidney Function ◽  
Cox Regression ◽  
Kidney Diseases ◽  
Early Event ◽  
Tubular Necrosis ◽  
Kidney Replacement Therapy ◽  
Maintenance Dialysis ◽  
One Year ◽  
End Stage

Abstract Background Literature on recovery of kidney function (RKF) in patients with end-stage kidney disease treated with maintenance dialysis (i.e. over 90 days) is limited. We assessed the incidence of RKF and its associated characteristics in a European cohort of dialysis patients. Methods We included adult patients from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry who started maintenance dialysis in 1997-2016. Sustained RKF was defined as permanent discontinuation of dialysis. Temporary discontinuation of ≥ 30 days (non-sustained RKF) was also evaluated. Factors associated with RKF adjusted for potential confounders were studied using Cox-regression analyses. Results RKF occurred in 7,657 (1.8%) of 440,996 patients of whom 71% experienced sustained RKF. Approximately 90% of all recoveries occurred within the first two years after day 91 of dialysis. Of patients with non-sustained RKF, 39% restarted kidney replacement therapy within one year. Sustained RKF was strongly associated with the following underlying kidney diseases (as registered by the treating physician): tubular necrosis (irreversible) or cortical necrosis (adjusted Hazard Ratio [aHR]: 20.4, 95%CI: 17.9-23.1), systemic sclerosis (aHR: 18.5, 95%CI: 13.8-24.7) and hemolytic uremic syndrome (aHR: 17.3, 95%CI: 13.9-21.6). Weaker associations were found for hemodialysis as first dialysis-modality (aHR: 1.5, 95%CI: 1.4-1.6) and dialysis initiation at an older age (aHR: 1.8, 95%CI: 1.6-2.0) or in a more recent time-period (aHR: 2.4, 95%CI: 2.1-2.7). Conclusions Definitive discontinuation of maintenance dialysis is a rare and not necessarily an early event. Certain clinical characteristics, but mostly the type of underlying kidney disease, are associated with a higher likelihood of RKF.

scholarly journals Clusterin deficiency induces lipid accumulation and tissue damage in kidney

2018 ◽  
Vol 237 (2) ◽  
pp. 175-191 ◽  
Author(s):  
Jung-Yoon Heo ◽  
Ji-Eun Kim ◽  
Yongwook Dan ◽  
Yong-Woon Kim ◽  
Jong-Yeon Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Kidney Disease ◽  
Lipid Metabolism ◽  
Kidney Disease ◽  
Lipid Accumulation ◽  
Transforming Growth Factor ◽  
Lipid Levels ◽  
Lipogenic Gene ◽  
Lipogenic Gene Expression ◽  
Deficient Mice

Clusterin is a secretory glycoprotein that is involved in multiple physiopathological processes, including lipid metabolism. Previous studies have shown that clusterin prevents hepatic lipid accumulation via suppression of sterol regulatory element-binding protein (SREBP) 1. In this study, we examined the role of clusterin in renal lipid accumulation in clusterin-knockout mice and NRK52e tubular epithelial cells. Clusterin deficiency increased the expression of SREBP1 and its target genes and decreased malonyl-CoA decarboxylase protein levels in the kidney. Expression of the endocytic receptor, megalin, and scavenger receptor class A was increased in clusterin-deficient mice. Functional analysis of lipid metabolism also revealed that lipid uptake and triglyceride synthesis were increased and fatty acid oxidation was reduced, leading to increased lipid accumulation in clusterin-deficient mice. These phenomena were accompanied by mesangial expansion, fibrosis and increased urinary protein-to-creatinine ratio. High-fat feeding aggravated these clusterin deficiency-induced pathological changes. Clusterin knockdown in NRK52e cells increased lipogenic gene expression and lipid levels, whereas overexpression of clusterin by treatment with adenovirus or recombinant clusterin protein suppressed lipogenic gene expression and lipid levels. Transforming growth factor-beta 1 (TGFB1) expression increased in the kidney of clusterin-deficient mice and suppression of TGFB1 in NRK52e cells suppressed lipid accumulation. These results suggest that clusterin deficiency induces renal lipid accumulation by dysregulating the expression of lipid metabolism-related factors and TGFB1, thereby leading to chronic kidney disease. Hence, clusterin may serve as a therapeutic target for lipid-induced chronic kidney disease.

scholarly journals The role of soluble urokinase-type Plasminogen Activator Receptor (suPAR) in Chronic Kidney Disease

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Ade Yonata ◽  
Ian Effendi ◽  
Zulkhair Ali ◽  
Novadian Suhaimi ◽  
S Suprapti
Keyword(s):  
Diabetic Nephropathy ◽  
Kidney Disease ◽  
Glomerular Filtration ◽  
Plasminogen Activator ◽  
Focal Segmental Glomerulosclerosis ◽  
Kidney Diseases ◽  
Glomerular Filtration Barrier ◽  
Filtration Barrier ◽  
Type Plasminogen Activator ◽  
Plasminogen Activator Receptor

Kidney disease affects 800 million children and adults worldwide, and the numbers keep increasing. A better understanding of the pathogenesis in kidney diseases, especially on a biomolecular level, is much needed to identify novel biomarkers and therapeutic targets for kidney diseases. The glomerular filtration barrier comprises endothelial cells, the glomerular basement membrane, and podocytes. The podocyte has a central role in part of the glomerular filtration barrier. The nor­mal functioning of podocytes is particularly important in preventing the heavy proteinuria seen in nephrotic syndrome or diabetic nephropathy, or in the disease process of focal segmental glomerulosclerosis. The podocyte is injured by circulating factors, which final­ly results in deranged podocyte motility. Soluble uro­kinase-type plasminogen activator receptor (suPAR) is a circulating form of glycosyl-phosphatidylinositol uPAR domain membrane protein and is known to play a role in the pathogenesis in kidney diseases, specifi­cally focal segmental glomerulosclerosis and diabetic nephropathy. suPAR binds to αvβ3 integrin on podo­cyte foot processes and causes podocyte structure dis­organization leading to glomerular filtration disruption and hence proteinuria. suPAR is also a potential bio­marker to predict the incidence of CKD.

scholarly journals The complicated role of mitochondria in the podocyte

2020 ◽  
Vol 319 (6) ◽  
pp. F955-F965
Author(s):  
Nehaben A. Gujarati ◽  
Jessica M. Vasquez ◽  
Daniel F. Bogenhagen ◽  
Sandeep K. Mallipattu
Keyword(s):  
Kidney Disease ◽  
Oxidative Phosphorylation ◽  
Diabetic Kidney Disease ◽  
Kidney Diseases ◽  
Redox Homeostasis ◽  
Experimental Models ◽  
Glomerular Diseases ◽  
Podocyte Injury ◽  
Atp Generation

Mitochondria play a complex role in maintaining cellular function including ATP generation, generation of biosynthetic precursors for macromolecules, maintenance of redox homeostasis, and metabolic waste management. Although the contribution of mitochondrial function in various kidney diseases has been studied, there are still avenues that need to be explored under healthy and diseased conditions. Mitochondrial damage and dysfunction have been implicated in experimental models of podocytopathy as well as in humans with glomerular diseases resulting from podocyte dysfunction. Specifically, in the podocyte, metabolism is largely driven by oxidative phosphorylation or glycolysis depending on the metabolic needs. These metabolic needs may change drastically in the presence of podocyte injury in glomerular diseases such as diabetic kidney disease or focal segmental glomerulosclerosis. Here, we review the role of mitochondria in the podocyte and the factors regulating its function at baseline and in a variety of podocytopathies to identify potential targets for therapy.

scholarly journals The Role of Podocytes and Podocyte-Associated Biomarkers in Diagnosis and Treatment of Diabetic Kidney Disease

2020 ◽  
Vol 4 (4) ◽  
Author(s):  
Igor Kravets ◽  
Sandeep K Mallipattu
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Public Health Problem ◽  
Diabetic Patients ◽  
Tubular Damage ◽  
Preventative Care ◽  
Important Public Health Problem ◽  
Podocyte Injury ◽  
Diabetic Kidney ◽  
Filtration Barrier

Abstract Diabetic kidney disease (DKD) is an important public health problem. Podocyte injury is a central event in the mechanism of DKD development. Podocytes are terminally differentiated, highly specialized glomerular visceral epithelial cells critical for the maintenance of the glomerular filtration barrier. Although potential mechanisms by which diabetic milieu contributes to irreversible loss of podocytes have been described, identification of markers that prognosticate either the development of DKD or the progression to end-stage kidney disease (ESKD) have only recently made it to the forefront. Currently, the most common marker of early DKD is microalbuminuria; however, this marker has significant limitations: not all diabetic patients with microalbuminuria will progress to ESKD and as many as 30% of patients with DKD have normal urine albumin levels. Several novel biomarkers indicating glomerular or tubular damage precede microalbuminuria, suggesting that the latter develops when significant kidney injury has already occurred. Because podocyte injury plays a key role in DKD pathogenesis, identification of markers of early podocyte injury or loss may play an important role in the early diagnosis of DKD. Such biomarkers in the urine include podocyte-released microparticles as well as expression of podocyte-specific markers. Here, we review the mechanisms by which podocyte injury contributes to DKD as well as key markers that have been recently implicated in the development and/or progression of DKD and might serve to identify individuals that require earlier preventative care and treatment in order to slow the progression to ESKD.

scholarly journals Deficiency of Mitochondrial Glycerol 3-Phosphate Dehydrogenase Exacerbates Podocyte Injury and the Progression of Diabetic Kidney Disease

2021 ◽  
Author(s):  
Hua Qu ◽  
Xiaoli Gong ◽  
Xiufei Liu ◽  
Rui Zhang ◽  
Yuren Wang ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mitochondrial Function ◽  
Diabetic Kidney Disease ◽  
Kidney Diseases ◽  
Ros Generation ◽  
Glomerular Injury ◽  
Inner Mitochondrial Membrane ◽  
Podocyte Injury ◽  
Diabetic Kidney ◽  
Glycerol 3 Phosphate Dehydrogenase

Mitochondrial function is essential for bioenergetics, metabolism and signaling and is compromised in diseases such as proteinuric kidney diseases, <a>contributing</a> to the global burden of kidney failure, cardiovascular morbidity and death. The key cell <a>type</a> that prevents proteinuria is the terminally differentiated glomerular podocyte. Here, we <a>characterized</a> the importance of mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH), located on the inner mitochondrial membrane, in regulating podocyte function and glomerular disease. Specifically, podocyte-dominated mGPDH expression was downregulated in the glomeruli of patients and mice with diabetic kidney disease and adriamycin nephropathy. Podocyte-specific depletion of mGPDH in mice exacerbated <a>diabetes-</a> or adriamycin-induced proteinuria, podocyte injury and glomerular pathology. RNA sequencing revealed that mGPDH regulated the RAGE signaling pathway, and inhibition of RAGE or its ligand, S100A10, protected against the impaired mitochondrial bioenergetics and increased ROS generation caused by mGPDH knockdown in cultured podocytes. Moreover, RAGE deletion in podocytes attenuated nephropathy progression in mGPDH-deficient diabetic mice. Rescue of podocyte mGPDH expression in mice with established glomerular injury <a>significantly improved</a> their renal function. In summary, our study proposes that activation of mGPDH induces mitochondrial biogenesis and reinforces mitochondrial function, which may provide a potential therapeutic target for preventing podocyte injury and proteinuria in diabetic kidney disease.

scholarly journals Deficiency of Mitochondrial Glycerol 3-Phosphate Dehydrogenase Exacerbates Podocyte Injury and the Progression of Diabetic Kidney Disease

2021 ◽  
Author(s):  
Hua Qu ◽  
Xiaoli Gong ◽  
Xiufei Liu ◽  
Rui Zhang ◽  
Yuren Wang ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mitochondrial Function ◽  
Diabetic Kidney Disease ◽  
Kidney Diseases ◽  
Ros Generation ◽  
Glomerular Injury ◽  
Inner Mitochondrial Membrane ◽  
Podocyte Injury ◽  
Diabetic Kidney ◽  
Glycerol 3 Phosphate Dehydrogenase

Mitochondrial function is essential for bioenergetics, metabolism and signaling and is compromised in diseases such as proteinuric kidney diseases, <a>contributing</a> to the global burden of kidney failure, cardiovascular morbidity and death. The key cell <a>type</a> that prevents proteinuria is the terminally differentiated glomerular podocyte. Here, we <a>characterized</a> the importance of mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH), located on the inner mitochondrial membrane, in regulating podocyte function and glomerular disease. Specifically, podocyte-dominated mGPDH expression was downregulated in the glomeruli of patients and mice with diabetic kidney disease and adriamycin nephropathy. Podocyte-specific depletion of mGPDH in mice exacerbated <a>diabetes-</a> or adriamycin-induced proteinuria, podocyte injury and glomerular pathology. RNA sequencing revealed that mGPDH regulated the RAGE signaling pathway, and inhibition of RAGE or its ligand, S100A10, protected against the impaired mitochondrial bioenergetics and increased ROS generation caused by mGPDH knockdown in cultured podocytes. Moreover, RAGE deletion in podocytes attenuated nephropathy progression in mGPDH-deficient diabetic mice. Rescue of podocyte mGPDH expression in mice with established glomerular injury <a>significantly improved</a> their renal function. In summary, our study proposes that activation of mGPDH induces mitochondrial biogenesis and reinforces mitochondrial function, which may provide a potential therapeutic target for preventing podocyte injury and proteinuria in diabetic kidney disease.

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