Podocytes and Proteinuric Kidney Disease

Abstract Glomerular disease is the most common cause of endstage renal disease (ESRD), accounting for almost two thirds of cases. In glomerular disease, alterations of po-docytes are of particular importance. Podocyte loss represents a central mediator of glomerular sclerosis. Toxic, genetic, immune, infectious, oxidant, metabolic, hemody-namic, and other mechanisms can all target the podo-cytes. These mechanisms provide new insight into the unique dynamic microenvironment that each individual podocyte inhabits and how it can turn hostile to survival. At the same time, they raise new therapeutic challenges to preserve glomerular function by containing podocyte injury and limiting its spread, both in podo-cytopathies and in other progressive glomerular diseases. Treatment strategies should aim at enhancing podocyte survival. The renin-angiotensin axis blockade, apart from its antifibrotic and intraglomerular hemodynamic effects, has an important role in preventing podocyte loss. However, only long-term observational studies can clarify if many patients will benefit from podocyte-targeted treatment such as abatacept or similar agents.

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The podocyte as a direct target for treatment of glomerular disease?

AJP Renal Physiology ◽

10.1152/ajprenal.00184.2016 ◽

2016 ◽

Vol 311 (1) ◽

pp. F46-F51 ◽

Cited By ~ 32

Author(s):

Sandeep K. Mallipattu ◽

John C. He

Keyword(s):

The United States ◽

Glomerular Disease ◽

Glomerular Sclerosis ◽

Systemic Effects ◽

Glomerular Diseases ◽

Podocyte Injury ◽

Filtration Barrier ◽

Focal Segmental Glomerular Sclerosis ◽

Control And Prevention ◽

Segmental Glomerular Sclerosis

The Centers for Disease Control and Prevention estimates more than 10% of adults in the United States, over 20 million Americans, have chronic kidney disease (CKD). A failure to maintain the glomerular filtration barrier directly contributes to the onset of CKD. The visceral epithelial cells, podocytes, are integral to the maintenance of this renal filtration barrier. Direct podocyte injury contributes to the onset and progression of glomerular diseases such as minimal change disease (MCD), focal segmental glomerular sclerosis (FSGS), diabetic nephropathy, and HIV-associated nephropathy (HIVAN). Since podocytes are terminally differentiated with minimal capacity to self-replicate, they are extremely sensitive to cellular injury. In the past two decades, our understanding of the mechanism(s) by which podocyte injury occurs has greatly expanded. With this newfound knowledge, therapeutic strategies have shifted to identifying targets directed specifically at the podocyte. Although the systemic effects of these agents are important, their direct effect on the podocyte proves to be essential in ameliorating glomerular disease. In this review, we highlight the mechanisms by which these agents directly target the podocyte independent of its systemic effects.

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Podocyte injury: the role of proteinuria, urinary plasminogen, and oxidative stress

AJP Renal Physiology ◽

10.1152/ajprenal.00162.2016 ◽

2016 ◽

Vol 311 (6) ◽

pp. F1308-F1317 ◽

Cited By ~ 28

Author(s):

Leopoldo Raij ◽

Runxia Tian ◽

Jenny S. Wong ◽

John C. He ◽

Kirk N. Campbell

Keyword(s):

Oxidative Stress ◽

Glomerular Filtration ◽

Biologically Active ◽

Current Evidence ◽

Glomerular Sclerosis ◽

Glomerular Diseases ◽

Podocyte Injury ◽

Filtration Barrier ◽

Focal Segmental Glomerular Sclerosis

Podocytes are the key target for injury in proteinuric glomerular diseases that result in podocyte loss, progressive focal segmental glomerular sclerosis (FSGS), and renal failure. Current evidence suggests that the initiation of podocyte injury and associated proteinuria can be separated from factors that drive and maintain these pathogenic processes leading to FSGS. In nephrotic urine aberrant glomerular filtration of plasminogen (Plg) is activated to the biologically active serine protease plasmin by urokinase-type plasminogen activator (uPA). In vivo inhibition of uPA mitigates Plg activation and development of FSGS in several proteinuric models of renal disease including 5/6 nephrectomy. Here, we show that Plg is markedly increased in the urine in two murine models of proteinuric kidney disease associated with podocyte injury: Tg26 HIV-associated nephropathy and the Cd2ap −/− model of FSGS. We show that human podocytes express uPA and three Plg receptors: uPAR, tPA, and Plg-RKT. We demonstrate that Plg treatment of podocytes specifically upregulates NADPH oxidase isoforms NOX2/NOX4 and increases production of mitochondrial-dependent superoxide anion (O2−) that promotes endothelin-1 synthesis. Plg via O2− also promotes expression of the B scavenger receptor CD36 and subsequent increased intracellular cholesterol uptake resulting in podocyte apoptosis. Taken together, our findings suggest that following disruption of the glomerular filtration barrier at the onset of proteinuric disease, podocytes are exposed to Plg resulting in further injury mediated by oxidative stress. We suggest that chronic exposure to Plg could serve as a “second hit” in glomerular disease and that Plg is potentially an attractive target for therapeutic intervention.

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Role of NADPH Oxidase-Mediated Reactive Oxygen Species in Podocyte Injury

BioMed Research International ◽

10.1155/2013/839761 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 47

Author(s):

Shan Chen ◽

Xian-Fang Meng ◽

Chun Zhang

Keyword(s):

Reactive Oxygen Species ◽

Nadph Oxidase ◽

Epithelial To Mesenchymal Transition ◽

Kidney Diseases ◽

Treatment Strategies ◽

Reactive Oxygen ◽

Glomerular Sclerosis ◽

Oxygen Species ◽

Podocyte Injury ◽

Mesenchymal Transition

Proteinuria is an independent risk factor for end-stage renal disease (ESRD) (Shankland, 2006). Recent studies highlighted the mechanisms of podocyte injury and implications for potential treatment strategies in proteinuric kidney diseases (Zhang et al., 2012). Reactive oxygen species (ROS) are cellular signals which are closely associated with the development and progression of glomerular sclerosis. NADPH oxidase is a district enzymatic source of cellular ROS production and prominently expressed in podocytes (Zhang et al., 2010). In the last decade, it has become evident that NADPH oxidase-derived ROS overproduction is a key trigger of podocyte injury, such as renin-angiotensin-aldosterone system activation (Whaley-Connell et al., 2006), epithelial-to-mesenchymal transition (Zhang et al., 2011), and inflammatory priming (Abais et al., 2013). This review focuses on the mechanism of NADPH oxidase-mediated ROS in podocyte injury under different pathophysiological conditions. In addition, we also reviewed the therapeutic perspectives of NADPH oxidase in kidney diseases related to podocyte injury.

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Inactivation of mediator complex protein 22 in podocytes results in intracellular vacuole formation, podocyte loss and premature death

Scientific Reports ◽

10.1038/s41598-020-76870-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Patricia Q. Rodriguez ◽

David Unnersjö-Jess ◽

Sonia S. Zambrano ◽

Jing Guo ◽

Katja Möller-Hackbarth ◽

...

Keyword(s):

Critical Role ◽

Kidney Tissue ◽

Premature Death ◽

Glomerular Disease ◽

Mediator Complex ◽

Glomerular Diseases ◽

Vacuole Formation ◽

Podocyte Loss ◽

Complex Protein ◽

Intracellular Vacuole

AbstractPodocytes are critical for the maintenance of kidney ultrafiltration barrier and play a key role in the progression of glomerular diseases. Although mediator complex proteins have been shown to be important for many physiological and pathological processes, their role in kidney tissue has not been studied. In this study, we identified a mediator complex protein 22 (Med22) as a renal podocyte cell-enriched molecule. Podocyte-specific Med22 knockout mouse showed that Med22 was not needed for normal podocyte maturation. However, it was critical for the maintenance of podocyte health as the mice developed progressive glomerular disease and died due to renal failure. Detailed morphological analyses showed that Med22-deficiency in podocytes resulted in intracellular vacuole formation followed by podocyte loss. Moreover, Med22-deficiency in younger mice promoted the progression of glomerular disease, suggesting Med22-mediated processes may have a role in the development of glomerulopathies. This study shows for the first time that mediator complex has a critical role in kidney physiology.

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Metabolomics in Psychiatric Disorders: What We Learn from Animal Models

Metabolites ◽

10.3390/metabo10020072 ◽

2020 ◽

Vol 10 (2) ◽

pp. 72 ◽

Cited By ~ 6

Author(s):

Elke Humer ◽

Thomas Probst ◽

Christoph Pieh

Keyword(s):

Animal Models ◽

Psychiatric Disorders ◽

Treatment Strategies ◽

Mood Stabilizers ◽

Psychiatric Medication ◽

Mitochondrial Regulation ◽

Novel Treatment Strategies ◽

Insight Into ◽

Test Treatment

Biomarkers are a recent research target within biological factors of psychiatric disorders. There is growing evidence for deriving biomarkers within psychiatric disorders in serum or urine samples in humans, however, few studies have investigated this differentiation in brain or cerebral fluid samples in psychiatric disorders. As brain samples from humans are only available at autopsy, animal models are commonly applied to determine the pathogenesis of psychiatric diseases and to test treatment strategies. The aim of this review is to summarize studies on biomarkers in animal models for psychiatric disorders. For depression, anxiety and addiction disorders studies, biomarkers in animal brains are available. Furthermore, several studies have investigated psychiatric medication, e.g., antipsychotics, antidepressants, or mood stabilizers, in animals. The most notable changes in biomarkers in depressed animal models were related to the glutamate-γ-aminobutyric acid-glutamine-cycle. In anxiety models, alterations in amino acid and energy metabolism (i.e., mitochondrial regulation) were observed. Addicted animals showed several biomarkers according to the induced drugs. In summary, animal models provide some direct insights into the cellular metabolites that are produced during psychiatric processes. In addition, the influence on biomarkers due to short- or long-term medication is a noticeable finding. Further studies should combine representative animal models and human studies on cerebral fluid to improve insight into mental disorders and advance the development of novel treatment strategies.

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Urinary excretion of viable podocytes in health and renal disease

AJP Renal Physiology ◽

10.1152/ajprenal.00404.2002 ◽

2003 ◽

Vol 285 (1) ◽

pp. F40-F48 ◽

Cited By ~ 200

Author(s):

Stefanie U. Vogelmann ◽

W. James Nelson ◽

Bryan D. Myers ◽

Kevin V. Lemley

Keyword(s):

Cultured Cells ◽

Growth Behavior ◽

Glomerular Disease ◽

Glomerular Sclerosis ◽

Tunel Staining ◽

Healthy Controls ◽

Podocyte Loss ◽

The Difference ◽

Glomerular Tuft ◽

Quiescent Disease

The loss of glomerular visceral epithelial cells (podocytes) has been associated with the development of glomerular sclerosis and loss of renal function. Viability of podocytes recovered from urine of subjects with glomerular disease and of healthy controls was investigated by propidium iodide exclusion and TUNEL staining. Podocyte loss was quantified by cytospin. The growth behavior in culture of urinary cells and their expression of specific markers were examined. The majority of urinary podocytes are viable, although apoptosis occurs in about one-half of the cells. Patients with active glomerular disease excreted up to 388 podocytes/mg creatinine, whereas healthy controls and patients with quiescent disease generally excreted <0.5 podocytes/mg creatinine. The identity of cultured cells was confirmed by their morphology, growth behavior, and expression of podocyte-specific markers. The difference in growth behavior between healthy controls and subjects with active glomerular disease suggests that in active disease viable podocytes detach from the glomerular tuft due to local environmental factors rather than defects in the podocytes per se, whereas in healthy individuals mostly senescent podocytes are shed.

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Direct Oral Anticoagulants Reduce Hypercoagulopathy and Preserve Podocyte Function in an Experimental Model of Glomerular Disease

Blood ◽

10.1182/blood-2020-139889 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 26-26

Author(s):

Amanda P. Waller ◽

Katelyn J Wolfgang ◽

Tasha K Wilkie ◽

Sagar Bhayana ◽

Bryce A. Kerlin

Keyword(s):

Diphtheria Toxin ◽

Glomerular Disease ◽

Rodent Model ◽

Ckd Progression ◽

Glomerular Diseases ◽

Podocyte Injury ◽

Thrombotic Risk ◽

Randomized Controlled ◽

Glomerular Proteinuria

Proteinuric glomerular diseases are a leading cause of chronic kidney disease (CKD). Both pre-CKD glomerular disease and established CKD are major risk factors for thrombosis. Glomerular capillary podocyte injury is a key determinant of CKD progression and results in massive proteinuria accompanied by an acquired hypercoagulopathy that drives thrombotic risk. Unfortunately, the routine use of anticoagulant prophylaxis during glomerular proteinuria (GP) remains controversial due to both a lack of agreement regarding indications and no randomized controlled trial data demonstrating both safety and efficacy. We have recently used rat glomerular disease models to reveal that: (1) Proteinuria is directly correlated with hypercoagulopathy and in vivo thrombosis and (2) Thrombin, the key effector enzyme of the coagulation system, directly injures podocytes during proteinuria. What is not yet known is the ability of direct oral anticoagulant (DOAC) therapy to improve these important CKD and thrombosis outcomes. Thus, the aim of the present study is to determine if DOACs simultaneously reduce podocytopathy and enable effective thromboprophylaxis during GP. We hypothesized that DOACs would simultaneously preserve podocyte function and reduce hypercoagulopathy, in a podocyte-specific rodent model of glomerular disease. We utilized the podocin promotor-human diphtheria toxin receptor (pDTR) transgenic rat model to induce highly specific podocyte injury following a single I.P. injection of 50 ng/kg diphtheria toxin (DT). DT-induced proteinuria was subsequently treated daily by oral gavage with 1) Dabigatran (20 mg/kg; Dabi), 2) Rivaroxaban (3 mg/kg; Riva), or 3) Sham (saline) and compared to healthy controls (n=3-6/group). Morning spot urine and citrated plasma samples were collected from each group at day 10 post-DT. Endogenous Thrombin Potential (ETP) was measured by Technothrombin TGA assay, without and with DOAC-Stop reagent. Glomeruli were isolated from the kidney, dissociated into single-cell suspensions and analyzed by flow cytometry following immunofluorescent antibody and TUNEL staining. Both Dabi and Riva significantly reduced proteinuria (Fig A) and podocytopathy (TUNEL positive podocyte fraction; Fig B), while concomitantly correcting elevated ETP levels (Fig C open symbols). Addition of DOAC-Stop (Fig C closed symbols) revealed an insignificant (P=0.18) trend toward partial ETP reduction, consistent with DOAC-mediated reduction of the underlying GP-mediated hypercoagulopathy (via indirect, antiproteinuric effects). In conclusion, dabigatran and rivaroxaban reduce proteinuria and enhance podocyte health in concert with alleviation of the acquired hypercoagulopathy in a podocyte-specific rodent model of glomerular disease. Overall these data suggest DOAC treatment as a novel approach to simultaneously reduce both podocytopathy and thrombotic co-morbidities during glomerular disease. Additional experiments using this model to determine DOAC efficacy on in vivo thrombosis are in progress. Results from these preclinical studies should inform subsequent randomized controlled DOAC trials that may transform care for patients with glomerular disease by mitigating their risk of both CKD progression and thrombosis. Disclosures No relevant conflicts of interest to declare.

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TrkC Is Essential for Nephron Function and Trans-Activates Igf1R Signaling

Journal of the American Society of Nephrology ◽

10.1681/asn.2020040424 ◽

2020 ◽

pp. ASN.2020040424

Author(s):

Carolin Lepa ◽

Sascha Hoppe ◽

Antje Stöber ◽

Boris V. Skryabin ◽

Laura Katharina Sievers ◽

...

Keyword(s):

Tyrosine Kinase ◽

Glomerular Disease ◽

Tyrosine Kinase Receptor ◽

Glomerular Diseases ◽

Basement Membrane Thickening ◽

Neurotrophin 3 ◽

Podocyte Loss ◽

Nephron Development ◽

Igf1r Signaling ◽

Igf1 Receptor

BackgroundInjury to kidney podocytes often results in chronic glomerular disease and consecutive nephron malfunction. For most glomerular diseases, targeted therapies are lacking. Thus, it is important to identify novel signaling pathways contributing to glomerular disease. Neurotrophic tyrosine kinase receptor 3 (TrkC) is expressed in podocytes and the protein transmits signals to the podocyte actin cytoskeleton.MethodsNephron-specific TrkC knockout (TrkC-KO) and nephron-specific TrkC-overexpressing (TrkC-OE) mice were generated to dissect the role of TrkC in nephron development and maintenance.ResultsBoth TrkC-KO and TrkC-OE mice exhibited enlarged glomeruli, mesangial proliferation, basement membrane thickening, albuminuria, podocyte loss, and aspects of FSGS during aging. Igf1 receptor (Igf1R)–associated gene expression was dysregulated in TrkC-KO mouse glomeruli. Phosphoproteins associated with insulin, erb-b2 receptor tyrosine kinase (Erbb), and Toll-like receptor signaling were enriched in lysates of podocytes treated with the TrkC ligand neurotrophin-3 (Nt-3). Activation of TrkC by Nt-3 resulted in phosphorylation of the Igf1R on activating tyrosine residues in podocytes. Igf1R phosphorylation was increased in TrkC-OE mouse kidneys while it was decreased in TrkC-KO kidneys. Furthermore, TrkC expression was elevated in glomerular tissue of patients with diabetic kidney disease compared with control glomerular tissue.ConclusionsOur results show that TrkC is essential for maintaining glomerular integrity. Furthermore, TrkC modulates Igf-related signaling in podocytes.

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Treatment strategies for encephalopathy related to status epilepticus during slow sleep, a narrative review of the literature

Reviews in the Neurosciences ◽

10.1515/revneuro-2020-0020 ◽

2020 ◽

Vol 31 (7) ◽

pp. 793-802

Author(s):

Ke Zhang ◽

Yu Yan ◽

Tangfeng Su

Keyword(s):

Status Epilepticus ◽

Treatment Options ◽

Treatment Strategies ◽

Epileptic Activity ◽

Neurodevelopmental Deficits ◽

Slow Sleep ◽

Long Term Prognosis ◽

Insight Into ◽

Review Current

AbstractEncephalopathy related to Status Epilepticus during slow Sleep (ESES) is an age-dependent syndrome characterized by the appearance of neuropsychological and behavioral disorders associated with extreme activation of epileptic activity during sleep. The major goal of therapy in ESES is to prevent neuropsychological deficits. Effective therapy to reduce seizures and resolve the EEG pattern of status epilepticus during sleep (SES) may be crucial to improve long-term prognosis. However, whether to improve neurodevelopmental deficits by suppressing or eliminating SES remains unknown. The purpose of this article is to review current therapeutic options in ESES, in order to provide better alternatives. Treatment options consist of antiepileptic drugs, steroids, immunoglobulins, the ketogenic diet, and surgery. Maybe therapy targeted mechanisms can be developed with deep insight into the etiology of ESES.

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Glomerular Diseases in Diabetic Patients: Implications for Diagnosis and Management

Journal of Clinical Medicine ◽

10.3390/jcm10091855 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1855

Author(s):

Nestor Oliva-Damaso ◽

José María Mora-Gutiérrez ◽

Andrew S. Bomback

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Treatment Strategies ◽

Glomerular Disease ◽

Diabetic Patients ◽

Glomerular Diseases ◽

Diabetic Kidney ◽

Sodium Glucose Cotransporter ◽

Patients With Diabetes ◽

New Treatment

The prevalence of diabetes continues to rise worldwide. In addition to rising rates of diabetic kidney disease, we are also seeing a parallel rise in nondiabetic kidney disease among patients with diabetes. These nondiabetic lesions include focal segmental glomerulosclerosis, IgA nephropathy, membranous nephropathy, and other glomerular diseases. The management of diabetic kidney disease is rapidly evolving to include, beyond glycemic control and renin angiotensin inhibition, the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists. These and other new treatment strategies should be applicable to managing glomerular disease in diabetic patients to reduce toxicities associated with immunosuppression and, in particular, corticosteroids. The prevalence of glomerular disease in diabetic patients is underappreciated. Diagnosis and appropriately treating these diseases remain an important avenue to modify kidney outcomes in diabetic patients.

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