Podocyte dysfunction in aging - related glomerulosclerosis

Camici, Marcella

doi:10.2741/204

Cited by 25 publications

(18 citation statements)

References 123 publications

(125 reference statements)

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“…[23][24][25][26][27] Several studies have indicated that loss of podocytes plays an important role in age-related glomerulosclerosis. 26,[28][29][30] It was unclear until now whether lost podocytes were at least partially regenerated and if age-related glomerulosclerosis was, thus, caused by an insufficient replacement of podocytes. 31 The aged PEC-rtTA mice showed typical changes within the glomerulus associated with kidney aging 27 (i.e., mesangial matrix expansion, thickening of the GBM with formation of spikes/humps, proteinuria, and podocyte hypertrophy).…”

Section: Discussionmentioning

confidence: 99%

The Regenerative Potential of Parietal Epithelial Cells in Adult Mice

Berger¹,

Schulte²,

Kuppe³

et al. 2014

Journal of the American Society of Nephrology

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Previously, we showed that some podocytes in juvenile mice are recruited from cells lining Bowman's capsule, suggesting that parietal epithelial cells (PECs) are a progenitor cell population for podocytes. To investigate whether PECs also replenish podocytes in adult mice, PECs were genetically labeled in an irreversible fashion in 5-week-old mice. No significant increase in labeled podocytes was observed, even after 18 months. To accelerate a potential regenerative mechanism, progressive glomerular hypertrophy was induced by progressive partial nephrectomies. Again, no significant podocyte replenishment was observed. Rather, labeled PECs exclusively invaded segments of the tuft affected by glomerulosclerosis, consistent with our previous findings. We next reassessed PEC recruitment in juvenile mice using a different reporter mouse and confirmed significant recruitment of labeled PECs onto the glomerular tuft. Moreover, some labeled cells on Bowman's capsule expressed podocyte markers, and cells on Bowman's capsule were also directly labeled in juvenile podocyte-specific Pod-rtTA transgenic mice. In 6-week-old mice, however, cells on Bowman's capsule no longer expressed podocyte-specific markers. Similarly, in human kidneys, some cells on Bowman's capsule expressed the podocyte marker synaptopodin from 2 weeks to 2 years of age but not at 7 years of age. In summary, podocyte regeneration from PECs could not be detected in aging mice or models of glomerular hypertrophy. We propose that a small fraction of committed podocytes reside on Bowman's capsule close to the vascular stalk and are recruited onto the glomerular tuft during infancy to adolescence in mice and humans.

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Section: Discussionmentioning

confidence: 99%

The Regenerative Potential of Parietal Epithelial Cells in Adult Mice

Berger¹,

Schulte²,

Kuppe³

et al. 2014

Journal of the American Society of Nephrology

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“…Our data confirmed that TNF-α was a target gene of miR-130a-3p and miR-301a-3p. We also observed an inhibitory effect of si-TNF-α on HG-induced oxidative stress and apoposis in podocytes, which could increase intrarenal renin-angiotensin system (RAS) activity and reduce nitric oxide (NO) availability to trigger glomerular disease (36). Because TNF-α is involved in HG-induced podocytes dysfunction, our results suggest that miR-130a-3p or miR-301a-3p is likely to be a novel biomarker or new potent therapeutic target for podocytes injury-related renal disease.…”

Section: Discussionmentioning

confidence: 86%

Overexpression of miR‑130a‑3p/301a‑3p attenuates high glucose‑induced MPC5 podocyte dysfunction through suppression of TNF‑α signaling

Jiang

Wang²,

Liu

et al. 2017

Exp Ther Med

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Abstract. Tumor necrosis factor (TNF)-α has been reported to be important in glomerulonephritis, which is closely associated with podocyte dysfunction and apoptosis. However, the precise mechanisms by which TNF-α expression are regulated remain unclear. The purpose of the present study was to investigate the role of microRNA (miR)-130a-3p/301a-3p in the post-transcriptional control of TNF-α expression and high glucose (HG)-induced podocyte dysfunction. Mice MPC5 podocytes were incubated with HG and transfected with miR-130a-3p/301a-3p mimics or inhibitors, reactive oxygen species (ROS) levels were measured by flow cytometry assay, and the mRNA and protein levels were assayed by using reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The targeted genes were predicted by a bioinformatics algorithm and verified using a dual luciferase reporter assay. It was observed that miR-130a-3p/301a-3p was a novel regulator of TNF-α in mouse podocytes. miR-130a-3p/301a-3p mimics inhibited TNF-α 3'-untranslated region luciferase reporter activity, in addition to endogenous TNF-α protein expression. Furthermore, forced expression of miR-130a-3p or miR-301a-3p resulted in the downregulation of ROS and malondialdehyde (MDA) and the upregulation of superoxide dismutase (SOD) 1 in the presence of HG. Inhibition of TNF-α level prevented a remarkable reduc tion in SOD activity and a marked increase in ROS and MDA levels in HG-treated podocytes. Furthermore, TNF-α loss-of-function significantly reversed HG-induced podocyte apoptosis. These data demonstrated a novel up-stream role for miR-130a-3p/301a-3p in TNF-α-mediated podocyte dysfunction and apoptosis in the presence of HG. IntroductionGlomerular podocytes are highly differentiated cells that play a key role in maintaining the integrity of the glomerular filtration barrier (1). In glomerular diseases, podocyte damage leads to increased glomerular barrier pore size, allowing the passage of proteins or other mediators to the tubular lumen, which results in proteinuria and progressive loss of kidney function (2). Accumulating evidence indicates that hyperglycemia contributes to podocyte lesions (3). Clinical data demonstrate that podocyte integrity is impaired, and the decreased podocyte number is confirmed in individuals with type 1 (T1DM) and 2 diabetes mellitus (T2DM) (4,5). In cultured podocytes, high glucose induces apoptosis, epithelial-mesenchymal transition (EMT), mitochondrial fission and autophagy through different signaling pathways (6-9). However, the underlying molecular mechanisms of high glucose-induced MPC5 podocytes dysfunction remain to be fully elucidated.MicroRNAs (miRs) are endogenous, noncoding, short, single-stranded RNAs (18-25 nucleotides) that are evolutionarily highly conserved, believed to regulate the translation of target messenger RNAs (mRNAs) by binding to its 3'-untranslated regions (3'-UTRs) and verified to play a role in controlling a variety of biological processes (10). Recently, several studies have h...

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“…Proteinuria is an hallmark of ORG and the podocyte is the common treath of proteinuric disease (122). Although lifestyle modification (salt restriction, hypocaloric diet and regular aerobic exercise) and angiotensin-converting enzyme inhibitors have shown benefical effects on obesity-associated proteinuria, only weight loss in early stages of the disease remains the most effective measure to definitely control proteinuria (124).…”

Section: Pharmacologic Targeting Of Podocyte Injury In Obesity-relmentioning

confidence: 99%

Anaplastic Lymphoma Kinase activating mechanisms and signaling pathways

Camici

Galetta²,

Abraham³

et al. 2015

Front Biosci

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Obesity-related glomerulopathy (ORG) is morphologically defined as focal segmental glomerulosclerosis and glomerulomegaly. Podocyte hypertrophy and reduced density are related to proteinuria which in a portion of patients is in the nephrotic range and evolvs towards renal failure. This article reviews the pathogenetic mechanisms of podocyte injury or dysfunction and lists new possible antiproteinuric strategies based on pharmaceutical targeting of the reported pathogenetic mechanisms. The pathogenetic mechnisms discussed include: renin angiotensin system, plasminogen activation inhibitor-1 (PAI-1), lipid metabolism, adiponectin, macrophages and proinflammatory cytokines, oxidative stress. The proposed antiproteinuric strategies include: AT2 receptor blockers; adipokine complement C19 TNF-related protein-1 blocker; selective PAI-1 inhibitor; farnesoid x receptor activation; increase of circulating adiponectin; selective antiinflammatory drugs; more potent antioxidants (Heme oxigenase, NOX4 inhibitors). However, because ORG is a rare disease, the need for a long term pharmaceutical approach in obese proteinuric patients should be carefully evaluated and limited to the cases with progressive loss of renal function.

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Podocyte dysfunction in aging - related glomerulosclerosis

Cited by 25 publications

References 123 publications

The Regenerative Potential of Parietal Epithelial Cells in Adult Mice

The Regenerative Potential of Parietal Epithelial Cells in Adult Mice

Overexpression of miR‑130a‑3p/301a‑3p attenuates high glucose‑induced MPC5 podocyte dysfunction through suppression of TNF‑α signaling

Anaplastic Lymphoma Kinase activating mechanisms and signaling pathways

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