scholarly journals Understanding the Mechanisms of Proteinuria: Therapeutic Implications

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Jorge E. Toblli ◽  
P. Bevione ◽  
F. Di Gennaro ◽  
L. Madalena ◽  
G. Cao ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Glomerular Filtration ◽  
Strong Predictor ◽  
Large Body ◽  
Glomerular Filtration Barrier ◽  
Glomerular Diseases ◽  
Filtration Barrier ◽  
Wide Range

A large body of evidence indicates that proteinuria is a strong predictor of morbidity, a cause of inflammation, oxidative stress and progression of chronic kidney disease, and development of cardiovascular disease. The processes that lead to proteinuria are complex and involve factors such as glomerular hemodynamic, tubular absorption, and diffusion gradients. Alterations in various different molecular pathways and interactions may lead to the identical clinical end points of proteinuria and chronic kidney disease. Glomerular diseases include a wide range of immune and nonimmune insults that may target and thus damage some components of the glomerular filtration barrier. In many of these conditions, the renal visceral epithelial cell (podocyte) responds to injury along defined pathways, which may explain the resultant clinical and histological changes. The recent discovery of the molecular components of the slit diaphragm, specialized structure of podocyte-podocyte interaction, has been a major breakthrough in understanding the crucial role of the epithelial layer of the glomerular barrier and the pathogenesis of proteinuria. Thispaper provides an overview and update on the structure and function of the glomerular filtration barrier and the pathogenesis of proteinuria, highlighting the role of the podocyte in this setting. In addition, current antiproteinuric therapeutic approaches are briefly commented.

Endoplasmic reticulum stress inhibition limits the progression of chronic kidney disease in the Dahl salt-sensitive rat

2017 ◽  
Vol 312 (1) ◽  
pp. F230-F244 ◽  
Author(s):  
Victoria Yum ◽  
Rachel E. Carlisle ◽  
Chao Lu ◽  
Elise Brimble ◽  
Jasmine Chahal ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Endoplasmic Reticulum ◽  
Kidney Disease ◽  
Er Stress ◽  
Glomerular Filtration ◽  
Renal Pathology ◽  
Myogenic Response ◽  
Glomerular Filtration Barrier ◽  
Chemical Chaperone ◽  
Filtration Barrier

Proteinuria is one of the primary risk factors for the progression of chronic kidney disease (CKD) and has been implicated in the induction of endoplasmic reticulum (ER) stress. We hypothesized that the suppression of ER stress with a low molecular weight chemical chaperone, 4-phenylbutyric acid (4-PBA), would reduce the severity of CKD and proteinuria in the Dahl salt-sensitive (SS) hypertensive rat. To induce hypertension and CKD, 12-wk-old male rats were placed on a high-salt (HS) diet for 4 wk with or without 4-PBA treatment. We assessed blood pressure and markers of CKD, including proteinuria, albuminuria, and renal pathology. Furthermore, we determined if HS feeding resulted in an impaired myogenic response, subsequent to ER stress. 4-PBA treatment reduced salt-induced hypertension, proteinuria, and albuminuria and preserved myogenic constriction. Furthermore, renal pathology was reduced with 4-PBA treatment, as indicated by lowered expression of profibrotic markers and fewer intratubular protein casts. In addition, ER stress in the glomerulus was reduced, and the integrity of the glomerular filtration barrier was preserved. These results suggest that 4-PBA treatment protects against proteinuria in the SS rat by preserving the myogenic response and by preventing ER stress, which led to a breakdown in the glomerular filtration barrier. As such, alleviating ER stress serves as a viable therapeutic strategy to preserve kidney function and to delay the progression of CKD in the animal model under study.

Cell Biology of the Glomerular Podocyte

2003 ◽  
Vol 83 (1) ◽  
pp. 253-307 ◽  
Author(s):  
Hermann Pavenstädt ◽  
Wilhelm Kriz ◽  
Matthias Kretzler
Keyword(s):  
Glomerular Filtration ◽  
Cell Biology ◽  
Considerable Increase ◽  
Gene Products ◽  
Common Theme ◽  
Glomerular Filtration Barrier ◽  
Glomerular Diseases ◽  
Selective Permeability ◽  
Filtration Barrier

Glomerular podocytes are highly specialized cells with a complex cytoarchitecture. Their most prominent features are interdigitated foot processes with filtration slits in between. These are bridged by the slit diaphragm, which plays a major role in establishing the selective permeability of the glomerular filtration barrier. Injury to podocytes leads to proteinuria, a hallmark of most glomerular diseases. New technical approaches have led to a considerable increase in our understanding of podocyte biology including protein inventory, composition and arrangement of the cytoskeleton, receptor equipment, and signaling pathways involved in the control of ultrafiltration. Moreover, disturbances of podocyte architecture resulting in the retraction of foot processes and proteinuria appear to be a common theme in the progression of acquired glomerular disease. In hereditary nephrotic syndromes identified over the last 2 years, all mutated gene products were localized in podocytes. This review integrates our recent physiological and molecular understanding of the role of podocytes during the maintenance and failure of the glomerular filtration barrier.

scholarly journals 1679 E/e predicts exercise capacity and adverse cardiovascular outcomes in patients with chronic kidney disease

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
G Gan ◽  
K Kadappu ◽  
A Bhat ◽  
F Fernandez ◽  
H Chen ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Exercise Capacity ◽  
Strong Predictor ◽  
Cardiovascular Death ◽  
Left Ventricular ◽  
Exercise Stress ◽  
Major Adverse Cardiovascular Events ◽  
Metabolic Equivalents

Abstract Funding Acknowledgements Nil OnBehalf NA Background Patients with chronic kidney disease(CKD) have reduced physical fitness that contributes to the disproportionately elevated risk of cardiovascular disease in this population. Our aim was to assess the association between E/e’ and exercise capacity in CKD patients and the prognostic role of E/e’. Methods Patients with Stage 3/4 CKD, without previous cardiac disease were prospectively recruited. Recruited patients underwent transthoracic echocardiogram and exercise stress echocardiogram with assessment of exercise E/e’. Patients were compared, one to one, to age, gender and risk factor matched controls and were followed annually for 5 years for cardiovascular death and major adverse cardiovascular events (MACE). Exercise capacity was assessed as metabolic equivalents (METs) with reduced exercise capacity defined as METS of ≤7. Raised exercise E/e’ was defined as exercise E/average e’ of >13. Results 156 CKD patients (62.8 ± 10.6 yrs, male 62%) were compared to 156 matched controls. CKD patients had higher rates of anemia (p < 0.01), larger left ventricular indexed mass (p < 0.01), larger LAVI (p < 0.01) and higher resting (p < 0.01) and exercise E/e’ (p < 0.01). Overall, CKD patients achieved lower METs (p < 0.01) with exercise and a greater proportion of CKD patients had METs ≤7 (p < 0.01). Receiver operating curves (Figure1) showed exercise E/e’ (AUC 0.89, CI 0.84-0.95, p < 0.01) to be the strongest predictor of reduced exercise capacity in CKD patients. Exercise E/e’ of >13 was also associated with higher rates of cardiovascular death and MACE amongst CKD patients. Conclusion Exercise E/e’ is a strong predictor of exercise capacity amongst CKD patients, who commonly have reduced exercise capacity presumably consequent to diastolic dysfunction. Raised exercise E/e’ in CKD patients is predictor of cardiovascular death and MACE. Abstract 1679 Figure.

scholarly journals Tensin2 is important for podocyte-glomerular basement membrane interaction and integrity of the glomerular filtration barrier

2020 ◽  
Vol 318 (6) ◽  
pp. F1520-F1530
Author(s):  
Kozue Uchio-Yamada ◽  
Keiko Yasuda ◽  
Yoko Monobe ◽  
Ken-ichi Akagi ◽  
Osamu Suzuki ◽  
...  
Keyword(s):  
Basement Membrane ◽  
Glomerular Filtration ◽  
Glomerular Basement Membrane ◽  
Dependent Manner ◽  
Glomerular Filtration Barrier ◽  
Filtration Barrier ◽  
Gbm Thickening ◽  
Strain Dependent ◽  
Deficient Mice

Tensin2 (Tns2), an integrin-linked protein, is enriched in podocytes within the glomerulus. Previous studies have revealed that Tns2-deficient mice exhibit defects of the glomerular basement membrane (GBM) soon after birth in a strain-dependent manner. However, the mechanisms for the onset of defects caused by Tns2 deficiency remains unidentified. Here, we aimed to determine the role of Tns2 using newborn Tns2-deficient mice and murine primary podocytes. Ultrastructural analysis revealed that developing glomeruli during postnatal nephrogenesis exhibited abnormal GBM processing due to ectopic laminin-α2 accumulation followed by GBM thickening. In addition, analysis of primary podocytes revealed that Tns2 deficiency led to impaired podocyte-GBM interaction and massive expression of laminin-α2 in podocytes. Our study suggests that weakened podocyte-GBM interaction due to Tns2 deficiency causes increased mechanical stress on podocytes by continuous daily filtration after birth, resulting in stressed podocytes ectopically producing laminin-α2, which interrupts GBM processing. We conclude that Tns2 plays important roles in the podocyte-GBM interaction and maintenance of the glomerular filtration barrier.

scholarly journals Early Glomerular Filtration Defect and Severe Renal Disease in Podocin-Deficient Mice

2004 ◽  
Vol 24 (2) ◽  
pp. 550-560 ◽  
Author(s):  
Séverine Roselli ◽  
Laurence Heidet ◽  
Mireille Sich ◽  
Anna Henger ◽  
Matthias Kretzler ◽  
...  
Keyword(s):  
Renal Disease ◽  
Glomerular Filtration ◽  
Molecular Mechanisms ◽  
Slit Diaphragm ◽  
Vascular Lesions ◽  
Suitable Model ◽  
Glomerular Diseases ◽  
Filtration Barrier ◽  
Severe Renal Disease

ABSTRACT Podocytes are specialized epithelial cells covering the basement membrane of the glomerulus in the kidney. The molecular mechanisms underlying the role of podocytes in glomerular filtration are still largely unknown. We generated podocin-deficient (Nphs2 −/−) mice to investigate the function of podocin, a protein expressed at the insertion of the slit diaphragm in podocytes and defective in a subset of patients with steroid-resistant nephrotic syndrome and focal and segmental glomerulosclerosis. Nphs2 −/− mice developed proteinuria during the antenatal period and died a few days after birth from renal failure caused by massive mesangial sclerosis. Electron microscopy revealed the extensive fusion of podocyte foot processes and the lack of a slit diaphragm in the remaining foot process junctions. Using real-time PCR and immunolabeling, we showed that the expression of other slit diaphragm components was modified in Nphs2 −/− kidneys: the expression of the nephrin gene was downregulated, whereas that of the ZO1 and CD2AP genes appeared to be upregulated. Interestingly, the progression of the renal disease, as well as the presence or absence of renal vascular lesions, depends on the genetic background. Our data demonstrate the crucial role of podocin in the establishment of the glomerular filtration barrier and provide a suitable model for mapping and identifying modifier genes involved in glomerular diseases caused by podocyte injuries.

scholarly journals Overexpression of TGF-β Inducible microRNA-143 in Zebrafish Leads to Impairment of the Glomerular Filtration Barrier by Targeting Proteoglycans

2016 ◽  
Vol 40 (5) ◽  
pp. 819-830 ◽  
Author(s):  
Janina Müller-Deile ◽  
Finn Gellrich ◽  
Heiko Schenk ◽  
Patricia Schroder ◽  
Jenny Nyström ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Glomerular Filtration ◽  
Cell Types ◽  
Endothelial Damage ◽  
Micro Rna ◽  
Glomerular Filtration Barrier ◽  
Glomerular Diseases ◽  
Filtration Barrier ◽  
Glomerular Endothelial Cells ◽  
Apoptotic Pathways

Background: TGF-β is known as an important stress factor of podocytes in glomerular diseases. Apart from activation of direct pro-apoptotic pathways we wanted to analyze micro-RNA (miRs) driven regulation of components involved in the integrity of the glomerular filtration barrier induced by TGF-β. Since miR-143-3p (miR-143) is described as a TGF-β inducible miR in other cell types, we examined this specific miR and its ability to induce glomerular pathology. Methods: We analyzed miR-143 expression in cultured human podocytes after stimulation with TGF-β. We also microinjected zebrafish eggs with a miR-143 mimic or with morpholinos specific for its targets syndecan and versican and compared phenotype and proteinuria development. Results: We detected a time dependent, TGF-β inducible expression of miR-143 in human podocytes. Targets of miR-143 relevant in glomerular biology are syndecans and versican, which are known components of the glycocalyx. We found that syndecan 1 and 4 were predominantly expressed in podocytes while syndecan 3 was largely expressed in glomerular endothelial cells. Versican could be detected in both cell types. After injection of a miR-143 mimic in zebrafish larvae, syndecan 3, 4 and versican were significantly downregulated. Moreover, miR-143 overexpression or versican knockdown by morpholino caused loss of plasma proteins, edema, podocyte effacement and endothelial damage. In contrast, knockdown of syndecan 3 and syndecan 4 had no effects on glomerular filtration barrier. Conclusion: Expression of versican and syndecan isoforms is indispensable for proper barrier function. Podocyte-derived miR-143 is a mediator for paracrine and autocrine cross talk between podocytes and glomerular endothelial cells and can alter expression of glomerular glycocalyx proteins.

scholarly journals A new function for parietal epithelial cells: a second glomerular barrier

2009 ◽  
Vol 297 (6) ◽  
pp. F1566-F1574 ◽  
Author(s):  
Takamoto Ohse ◽  
Alice M. Chang ◽  
Jeffrey W. Pippin ◽  
George Jarad ◽  
Kelly L. Hudkins ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Basement Membrane ◽  
Glomerular Filtration ◽  
Glomerular Filtration Barrier ◽  
Impermeable Barrier ◽  
Filtration Barrier ◽  
Proximal Tubular ◽  
Parietal Epithelial Cells ◽  
Glomerular Barrier

The functional role of glomerular parietal epithelial cells (PECs) remains poorly understood. To test the hypothesis that PECs form an impermeable barrier to filtered protein through the formation of tight junctions (TJ), studies were performed in normal animals and in the anti-glomerular basement membrane (GBM) model of crescentic nephritis. Electron microscopy showed well-defined TJ between PECs in normal mice, which no longer could be identified when these cells became extensively damaged or detached from their underlying Bowman's basement membrane. The TJ proteins claudin-1, zonula occludens-1, and occludin stained positive in PECs; however, staining decreased in anti-GBM disease. To show that these events were associated with increased permeability across the PEC-Bowman's basement membrane barrier, control and diseased animals were injected intravenously with either Texas red-conjugated dextran (3 kDa) or ovalbumin (45 kDa) tracers. As expected, both tracers were readily filtered across the glomerular filtration barrier and taken up by proximal tubular cells. However, when the glomerular filtration barrier was injured in anti-GBM disease, tracers were taken up by podocytes and PECs. Moreover, tracers were also detected between PECs and the underlying Bowman's basement membrane, and in many instances were detected in the extraglomerular space. We propose that together with its underlying Bowman's basement membrane, the TJ of PECs serve as a second barrier to protein. When disturbed following PEC injury, the increase in permeability of this layer to filtered protein is a mechanism underlying periglomerular inflammation characteristic of anti-GBM disease.

scholarly journals Use of Lipid-Modifying Agents for the Treatment of Glomerular Diseases

2021 ◽  
Vol 11 (8) ◽  
pp. 820
Author(s):  
Mengyuan Ge ◽  
Sandra Merscher ◽  
Alessia Fornoni
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Recent Progress ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Glomerular Diseases ◽  
Intracellular Lipids ◽  
Lipid Modifying Agents ◽  
Made In

Although dyslipidemia is associated with chronic kidney disease (CKD), it is more common in nephrotic syndrome (NS), and guidelines for the management of hyperlipidemia in NS are largely opinion-based. In addition to the role of circulating lipids, an increasing number of studies suggest that intrarenal lipids contribute to the progression of glomerular diseases, indicating that proteinuric kidney diseases may be a form of “fatty kidney disease” and that reducing intracellular lipids could represent a new therapeutic approach to slow the progression of CKD. In this review, we summarize recent progress made in the utilization of lipid-modifying agents to lower renal parenchymal lipid accumulation and to prevent or reduce kidney injury. The agents mentioned in this review are categorized according to their specific targets, but they may also regulate other lipid-relevant pathways.

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