The transcriptomic signature of the aging podocyte

Mukhi, Dhanunjay; Suszták, Katalin

doi:10.1016/j.kint.2020.08.004

Cited by 8 publications

(7 citation statements)

References 9 publications

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“…Although research on the mechanism of glomerular podocyte injury continues to advance, the prevention and treatment of glomerular podocyte injury and proteinuria are still di cult problems in clinical treatment. Recent studies have found that glomerular podocyte damage is an important event in the early stage of chronic kidney disease, and the identi cation effective and feasible methods for the treatment of podocyte damage is the key to solving this problem [1][2] .Our previous studies have found that the PI3K/Akt signal transduction pathway plays an important role in podocyte injury [3] . Phosphatase and tensin homolog (PTEN) is an important enzyme with lipid and protein phosphatase activities.PTEN is also a tumor suppressor.…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Dexamethasone reduces podocyte injury through the PTEN-PI3K/Akt signaling pathway

rRen

Zeng

et al. 2021

Preprint

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Objective: To study the role of Akt and its downstream molecules in the PTEN-PI3K/Akt signaling pathway, namely,GSK3β and Bad, in the Dexamethasone(DEX)-mediated regulation of PAN-induced glomerular podocyte injury and to elucidate the molecular mechanism of podocyte injury regulation. Methods: Glomerular podocytes (MPC5) were cultured in vitro and divided into four groups: the control group, PTEN silencing group (siPTEN group), puromycin group (PAN group), and puromycin group + DEX group (PAN+ DEX group). The cells in each group were treated for 8h, 24h, and 48h, and then, the experiment was carried out. The cells in the control group were cultured in RPMI 1640 with 0.02% DMSO, the cells in the siPTEN group were used to construct a silencing kit, the podocytes in the PAN group were treated with puromycin (final concentration of 50μg/ml), and the podocytes in the DEX+PAN group were pretreated with 0.1μmol/L DEX followed by PAN (final concentration of 50μg/ml). An inverted phase contrast microscope was used to observe the morphological changes in the podocytes and the changes in the cell body area in each group, laser confocal microscopy was used to detect the expression and distribution of the PTEN protein, and flow cytometry was used to detect and analyze the apoptosis rate and mitochondrial membrane potential of each group of podocytes. Western blot was used to detect the expression of the PTEN, P-Akt, Akt, P-GSK3β and GSK3β proteins in each group of podocytes, and transmission electron microscopy was used to observe the changes in the morphology and structure of each group of podocytes. Results: After PAN was used to injure the podocytes, the expression of the PTEN protein decreased, the rate of apoptosis increased, and the flux of autophagy was inhibited. DEX treatment reversed the changes described above.After PAN was used to injure the podocytes, the expression of p-Ak and p-GSK3β decreased, and DEX reversed these effects on the expression of p-Akt and p-GSK3β in the podocytes. Compared with the control group, in the PAN group, the mitochondria gradually swelled and rounded, mitochondrial cristae arrangement became disordered, mitochondrial autophagy was inhibited; DEX reversed the changes described above after the PTEN gene was silenced. Conclusion: This study confirmed that PAN can inhibit podocyte autophagy and induce podocyte damage. DEX can reduce the PAN-induced suppression of podocyte autophagy, enhance podocyte autophagy, and ameliorate podocyte damage. The protective mechanism may be through the upregulation of PTEN expression, which is achieved by inhibiting the activation of the PI3K/Akt signaling pathway.

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Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Dexamethasone reduces podocyte injury through the PTEN-PI3K/Akt signaling pathway

rRen

Zeng

et al. 2021

Preprint

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“…The proteinuria is characterized by the loss of podocytes, which leads to glomerulosclerosis and end-stage renal failure. The loss of more than 20% of podocytes causes irreversible glomerulosclerosis and a decrease in glomerular filtration rate (33,34). Yamaguchi et al proposed that EMT as a novel mechanism for podocyte loss (35).…”

Section: Discussionmentioning

confidence: 99%

ZEB2 transduces HIF1α dependent regulation of Transglutaminase 2 in glomerular podocytes

Pasupulati

2021

Preprint

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Glomerular podocytes are instrumental in ensuring glomerular permselectivity and regulating the integrity of glomerular biology. However, podocytes are vulnerable to various noxious stimuli such as hypoxia, and podocyte injury presented with glomerulosclerosis and impaired kidney function. The mechanism of hypoxia-induced podocyte injury vis-a-vis glomerulosclerosis has remained enigmatic. Hypoxia inducible factor 1α (HIF1α) that transduces hypoxic adaptations, induces Transglutaminase 2 (TG2), a calcium dependent enzyme that catalyzes intramolecular ε-(γ-glutamyl) lysine cross-links of extracellular matrix (ECM) proteins. In this study, we investigated the mechanism of regulation of TG2 by HIF1α. Stabilization of HIF1α by FG4592 (Roxadustat) and physiological hypoxia, resulted in elevated expression of ZEB2 (zinc-finger E-box-homeobox 2) and its downstream target TRPC6 (transient receptor potential channel 6). ZEB2 transcriptionally activates TG2 expression, whereas, via TRPC6, it induces calcium influx, inturn it increases the TG2 activity. Blocking the TRPC6 action or suppressing its expression only partially attenuated FG4592 induced TG2 activity, whereas suppression of ZEB2 expression significantly abolished TG2 activity. This study demonstrates that stabilization of HIF1α stimulates both TG2 expression and activity, whereas abrogation of HIF1α by metformin prevented HIF1α regulated TG2 and consequent glomerular injury.

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“…Since, macrophage accumulation predicts declined kidney function, the stimuli that skew macrophages into kidney needs to be investigated. It is noteworthy that kidneys display most signi cant age-related changes with accumulation of macrophages of M1-proin ammatory phenotype 11,12 .…”

Section: Introductionmentioning

confidence: 99%

Growth hormone induces TNF-α in podocytes and contributes to monocyte-to-macrophage differentiation: Implications in Diabetic kidney disease

Pasupulati

Nishad

Mukhi

et al. 2022

Preprint

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Diabetes shortens the life expectancy by more than a decade, and the excess mortality in diabetes is correlated with the incidence of kidney disease. Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. In human biopsies and experimental models of DKD, macrophage accumulation predicts the severity of kidney damage. The mechanism of macrophage accumulation in diabetic glomeruli, however, is unknown. Increased growth hormone (GH) levels in type 1 diabetes and acromegalic patients had deleterious effects on glomerular biology. GH-treated mice had significant podocyte injury, glomerulosclerosis as well as increased macrophages. This study investigated if human podocytes injured by a GH stimulus contributed to macrophage accumulation. Following GH treatment, TNF-α signaling was increased in podocytes, as determined by RNA-seq analysis. Conditioned media from GH-treated human podocytes induced differentiation of THP1 monocytes to macrophages. Depleting the TNF-α in conditioned media with neutralizing antibodies diminished the effect of conditioned media from GH-treated podocytes on monocytes. Conditioned media from GH-treated primary podocytes with depleted TNF-α levels fail to elicit monocyte-to-macrophage differentiation. Mice administered with GH displayed glomerular accumulation of macrophages, podocyte injury, and proteinuria. Renal biopsies from DKD patients demonstrated activated TNF-α signaling, macrophage accumulation, and fibrosis. Together, this study suggests TNF-α secreted by podocytes under the influence of GH could contribute to macrophage accumulation, thus eliciting adverse renal inflammation and impaired function. Our study suggests targeting GH and/or TNF-α signaling could be a therapeutic approach to combat DKD.

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The transcriptomic signature of the aging podocyte

Cited by 8 publications

References 9 publications

WITHDRAWN: Dexamethasone reduces podocyte injury through the PTEN-PI3K/Akt signaling pathway

WITHDRAWN: Dexamethasone reduces podocyte injury through the PTEN-PI3K/Akt signaling pathway

ZEB2 transduces HIF1α dependent regulation of Transglutaminase 2 in glomerular podocytes

Growth hormone induces TNF-α in podocytes and contributes to monocyte-to-macrophage differentiation: Implications in Diabetic kidney disease

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