scholarly journals The TRPC6-AMPK pathway is involved in cytoskeleton reorganization and glucose uptake in podocytes

2018 ◽  
Author(s):  
Patrycja Rachubik ◽  
Maria Szrejder ◽  
Dorota Rogacka ◽  
Irena Audzeyenka ◽  
Michał Rychłowski ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Glomerular Filtration ◽  
Glomerular Filtration Barrier ◽  
Filtration Barrier ◽  
Cytoskeleton Reorganization ◽  
Insulin Dependent ◽  
Trpc6 Channel ◽  
Amp Activated Protein Kinase ◽  
Glomerular Capillaries

AbstractPodocytes are dynamic polarized cells on the surface of glomerular capillaries that are an essential part of the glomerular filtration barrier. AMP-activated protein kinase (AMPK), a key regulator of glucose and fatty acid metabolism, plays a major role in obesity and type 2 diabetes. Accumulating evidence suggests that TRPC6 channels are crucial mediators of calcium transport in podocytes and are involved in regulating glomerular filtration barrier. Here we investigated whether the AMPK-TRPC6 pathway is involved in insulin-dependent cytoskeleton reorganization and glucose uptake in cultured rat podocytes. Insulin regulates the interaction of TRPC6 with AMPKα2 in cultured rat podocytes The results suggested a key role for the TRPC6 channel in the mediation of insulin-dependent activation of AMPKα2, actin cytoskeleton reorganization and glucose uptake in podocyte. Moreover, AMPK and TRPC6 activation were required to stimulate the Rac1 signaling pathway. These results suggest a potentially important new mechanism that regulates glucose transport in podocytes and that could be injurious during diabetes.

scholarly journals The TRPC6-AMPK Pathway is Involved in Insulin-Dependent Cytoskeleton Reorganization and Glucose Uptake in Cultured Rat Podocytes

2018 ◽  
Vol 51 (1) ◽  
pp. 393-410 ◽  
Author(s):  
Patrycja Rachubik ◽  
Maria Szrejder ◽  
Dorota Rogacka ◽  
Irena Audzeyenka ◽  
Michał Rychłowski ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Glomerular Filtration ◽  
Glucose Transport ◽  
Signaling Proteins ◽  
Filtration Barrier ◽  
Cytoskeleton Reorganization ◽  
Insulin Dependent ◽  
Trpc6 Channel ◽  
Amp Activated Protein Kinase

Background/Aims: Podocytes are dynamic polarized cells on the surface of glomerular capillaries that are an essential part of the glomerular filtration barrier. AMP-activated protein kinase (AMPK), a key regulator of glucose and fatty acid metabolism, plays a major role in obesity and type 2 diabetes. Accumulating evidence suggests that TRPC6 channels are crucial mediators of calcium transport in podocytes and are involved in regulating glomerular filtration. Here we investigated whether the AMPK-TRPC6 pathway is involved in insulin-dependent cytoskeleton reorganization and glucose uptake in cultured rat podocytes. Methods: Western blot and immunofluorescence analysis confirmed AMPKα and TRPC6 expression, the phosphorylation of proteins associated with actin cytoskeleton reorganization (PAK, rac1, and cofilin), and the expression of insulin signaling proteins (Akt, Insulin receptor). Coimmunoprecipitation and immunofluorescence results demonstrated AMPKα/TRPC6 interaction. To ask whether TRPC6 is involved in the insulin regulation of glucose transport, we measured insulin-dependent (1, 2-3H)-deoxy-D-glucose uptake into podocytes after reducing TRPC6 activity pharmacologically and biochemically (TRPC6 siRNA). Results: The results suggested a key role for the TRPC6 channel in the mediation of insulin-dependent activation of AMPKα2 and glucose uptake. Moreover, AMPK and TRPC6 activation were required to stimulate the Rac1 signaling pathway. Conclusion: These results suggest a potentially important new mechanism that regulates glucose transport in podocytes and that could be injurious during diabetes.

Permeability of Peritoneal and Glomerular Capillaries: What are the Differences According to Pore Theory?

2011 ◽  
Vol 31 (3) ◽  
pp. 249-258 ◽  
Author(s):  
Bengt Rippe ◽  
Simon Davies
Keyword(s):  
Glomerular Filtration ◽  
Matrix Theory ◽  
Complex Structure ◽  
Gel Filtration ◽  
Diffusion Path ◽  
Peritoneal Membrane ◽  
Glomerular Filtration Barrier ◽  
Filtration Barrier ◽  
Shed Light ◽  
Glomerular Capillaries

Pore and fiber-matrix theory can both be used to model the peritoneal and glomerular filtration barriers in an attempt to shed light on their differing structure–function relationships. The glomerular filtration barrier (GFB) is structurally more specialized, morphologically complex, and also highly dynamic; but paradoxically, because of its uniformity, it conforms more closely to the predictions of pore theory than does the peritoneum, and it in fact resembles a more simple synthetic membrane. Compared with the peritoneal capillary wall, the GFB has no transcellular “third” pores (aquaporins), and it is far less leaky and more size-selective to proteins, mainly as a result of having far fewer “large” pores. It does have charge-selective properties, although these are considered much less important in excluding albumin than was once thought, and it is also able to select polymers according to their shape and flexibility. Even this property might reflect the relative uniformity of the GFB, which has a high diffusion area and short diffusion distances, compared with the peritoneal barrier, which behaves more like a gel filtration column. Furthermore, the length of the diffusion path across the peritoneal membrane is much greater for small solutes, given the relatively high ultrafiltration coefficient for that membrane compared with the GFB—a situation that reflects both the tortuosity of the interendothelial clefts and the distribution of peritoneal capillaries within the interstitium. These comparisons reveal the peritoneal barrier as a relatively complex structure to model; and yet this model may be more representative of the general microcirculation, and thus shed light on systemic endothelial function in renal failure.

scholarly journals Sodium-Glucose Cotransporter-2 Inhibitors in Patients with Hereditary Podocytopathies, Alport Syndrome, and FSGS: A Case Series to Better Plan a Large-Scale Study

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1815
Author(s):  
Jan Boeckhaus ◽  
Oliver Gross
Keyword(s):  
Glomerular Filtration ◽  
Alport Syndrome ◽  
Large Scale ◽  
Case Series ◽  
Hereditary Diseases ◽  
Glomerular Filtration Barrier ◽  
Early Effect ◽  
Filtration Barrier ◽  
First Case ◽  
Sodium Glucose Cotransporter

Hereditary diseases of the glomerular filtration barrier are characterized by a more vulnerable glomerular basement membrane and dysfunctional podocytes. Recent clinical trials have demonstrated the nephroprotective effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in chronic kidney disease (CKD). SGLT2-mediated afferent arteriole vasoconstriction is hypothesized to correct the hemodynamic overload of the glomerular filtration barrier in hereditary podocytopathies. To test this hypothesis, we report data in a case series of patients with Alport syndrome and focal segmental glomerulosclerosis (FSGS) with respect of the early effect of SGLT2i on the kidney function. Mean duration of treatment was 4.5 (±2.9) months. Mean serum creatinine before and after SGLT-2i initiation was 1.46 (±0.42) and 1.58 (±0.55) mg/dL, respectively, with a median estimated glomerular filtration rate of 64 (±27) before and 64 (±32) mL/min/1.73 m2 after initiation of SGLT2i. Mean urinary albumin-creatinine ratio in mg/g creatinine before SGLT-2i initiation was 1827 (±1560) and decreased by almost 40% to 1127 (±854) after SGLT2i initiation. To our knowledge, this is the first case series on the effect and safety of SGLT2i in patients with hereditary podocytopathies. Specific large-scale trials in podocytopathies are needed to confirm our findings in this population with a tremendous unmet medical need for more effective, early on, and safe nephroprotective therapies.

scholarly journals Thrombomodulin is upregulated in the kidneys of women with pre-eclampsia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Cleo C. L. van Aanhold ◽  
Manon Bos ◽  
Katrina M. Mirabito Colafella ◽  
Marie-Louise P. van der Hoorn ◽  
Ron Wolterbeek ◽  
...  
Keyword(s):  
Glomerular Filtration ◽  
Early Stage ◽  
Vascular Inflammation ◽  
Angiogenesis Inhibitor ◽  
Serum Levels ◽  
Dependent Manner ◽  
Glomerular Filtration Barrier ◽  
Soluble Thrombomodulin ◽  
Filtration Barrier ◽  
Glomerular Endothelium

AbstractThe endothelial glycoprotein thrombomodulin regulates coagulation, vascular inflammation and apoptosis. In the kidney, thrombomodulin protects the glomerular filtration barrier by eliciting crosstalk between the glomerular endothelium and podocytes. Several glomerular pathologies are characterized by a loss of glomerular thrombomodulin. In women with pre-eclampsia, serum levels of soluble thrombomodulin are increased, possibly reflecting a loss from the glomerular endothelium. We set out to investigate whether thrombomodulin expression is decreased in the kidneys of women with pre-eclampsia and rats exposed to an angiogenesis inhibitor. Thrombomodulin expression was examined using immunohistochemistry and qPCR in renal autopsy tissues collected from 11 pre-eclamptic women, 22 pregnant controls and 11 hypertensive non-pregnant women. Further, kidneys from rats treated with increasing doses of sunitinib or sunitinib in combination with endothelin receptor antagonists were studied. Glomerular thrombomodulin protein levels were increased in the kidneys of women with pre-eclampsia. In parallel, in rats exposed to sunitinib, glomerular thrombomodulin was upregulated in a dose-dependent manner, and the upregulation of glomerular thrombomodulin preceded the onset of histopathological changes. Selective ETAR blockade, but not dual ETA/BR blockade, normalised the sunitinib-induced increase in thrombomodulin expression and albuminuria. We propose that glomerular thrombomodulin expression increases at an early stage of renal damage induced by antiangiogenic conditions. The upregulation of this nephroprotective protein in glomerular endothelial cells might serve as a mechanism to protect the glomerular filtration barrier in pre-eclampsia.

scholarly journals Nck Proteins Maintain the Adult Glomerular Filtration Barrier

2009 ◽  
Vol 20 (7) ◽  
pp. 1533-1543 ◽  
Author(s):  
Nina Jones ◽  
Laura A. New ◽  
Megan A. Fortino ◽  
Vera Eremina ◽  
Julie Ruston ◽  
...  
Keyword(s):  
Glomerular Filtration ◽  
Glomerular Filtration Barrier ◽  
Filtration Barrier

Abstract 516: Knockdown of the Hypertension Associated Gene NOSTRIN Alters Glomerular Barrier Function in Zebrafish (Danio rerio)

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Torsten Kirsch ◽  
Jessica Kaufeld ◽  
Ron Korstanje ◽  
Dirk Hentschel ◽  
Hermann Haller ◽  
...  
Keyword(s):  
Glomerular Filtration ◽  
Barrier Function ◽  
Morphological Changes ◽  
Glomerular Filtration Barrier ◽  
Cell Dysfunction ◽  
Larval Zebrafish ◽  
Filtration Barrier ◽  
Important Regulator ◽  
Glomerular Barrier ◽  
Prime Source

The bioavailability of nitric oxide (NO) has been associated with the development and progression of vascular and renal disease. NOSTRIN (for eNOS Traffic Inducer) has primarily been recognized as one important regulator of eNOS, the prime source of NO in the cardiovascular system, with a possible role in the pathogenesis of pre-eclampsia and the development of increased intrahepatic resistance in liver disease. Here, we identified NOSTRIN in the center of a QTL-overlap region in rat and human trait loci that are associated with hypertension. Glomerular NOSTRIN expression is detectable in podocytes in human and rat glomeruli and podocytic NOSTRIN expression is diminished in hypertensive kidney disease. We show that knockdown of NOSTRIN alters the glomerular filtration barrier function in larval zebrafish, inducing proteinuria and leading to ultrastructural morphological changes on the endothelial as well as epithelial side and the GBM of the glomerular capillary loop. We also demonstrate that NOSTRIN interacts with proteins associated with the podocyte slit membrane. We conclude that NOSTRIN expression is an important factor for the integrity of the glomerular filtration barrier. Disease related alteration of NOSTRIN expression may not only affect the vascular endothelium and therefore contribute to endothelial cell dysfunction but may also contribute to the development of podocyte disease and proteinuria.

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