New insight into podocyte slit diaphragm, a therapeutic target of proteinuria

Kawachi, Hiroshi; Fukusumi, Yoshiyasu

doi:10.1007/s10157-020-01854-3

Cited by 90 publications

(74 citation statements)

References 129 publications

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“…Podocytes are the largest intrinsic cell in the kidney.Early podocyte damage is reversible.Once the damaging factor is removed,the cytoskeleton proteins are repaired, and the foot processes still form a cross-connected pattern to perform their functions; however, if the damaging factor continues to act on podocytes,the podocyte damage irreversible [7][8] .The worst consequence is that the proliferative capacity of the podocytes is limited. Once damage occurs, podocytes cannot continue to perform their functions through self-compensation, forming a vicious circle and accelerating the damage of other podocytes, ultimately leading to the occurrence and development of proteinuria.…”

Section: Discussionmentioning

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WITHDRAWN: Dexamethasone reduces podocyte injury through the PTEN-PI3K/Akt signaling pathway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

confidence: 99%

WITHDRAWN: Dexamethasone reduces podocyte injury through the PTEN-PI3K/Akt signaling pathway

rRen

Zeng

et al. 2021

Preprint

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“…Further studies are needed to understand the effect of PAR2 on the regulation of slit diaphragm protein expression. A decrease in the protein level of nephrin, a key molecule forming a molecular sieve of the slit diaphragm, 38 was not restored by AZL in SHRSP.ZF rat kidney, though podocin was increased. The imbalance in the expression of these slit diaphragm proteins may be involved in unresolved proteinuria in AZL‐treated SHRSP.ZF rats.…”

Section: Discussionmentioning

confidence: 88%

Activation of protease‐activated receptor 2 is associated with blood pressure regulation and proteinuria reduction in metabolic syndrome

Maruyama‐Fumoto

McGuire

Fairlie

et al. 2020

Clin Exp Pharma Physio

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Metabolic syndrome (MetS) increases the risk of kidney disease. In SHRSP.Z‐Leprfa/IzmDmcr (SHRSP.ZF) rats with MetS, protease‐activated receptor 2 (PAR2)‐mediated vasorelaxation is preserved in the aorta at 20 weeks of age (weeks) via enhancement of nitric oxide production but impaired at 30 weeks by oxidative stress. However, impairment of PAR2‐mediated vasorelaxation of renal arteries and its possible implications for kidney disease are unclear. We used organ baths to assess PAR2‐mediated vasorelaxation of isolated renal arteries, colorimetric methods to measure urinary protein levels as an index of renal function, and western blot to determine expression of PAR2 and nephrin proteins in the kidneys of SHRSP.ZF rats at 10, 20, and 30 weeks. We assessed renal arteries and kidney function for effects of orally administered GB88, a pathway‐dependent PAR2 antagonist, from 10 to 18 weeks, and azilsartan, an angiotensin II type 1 receptor blocker, from 13 to 23 weeks. PAR2‐mediated vasorelaxation was slightly lower at 20 weeks and attenuated significantly at 30 weeks compared with those at 10 weeks. Urinary protein levels were increased at 20 and 30 weeks. Decreased protein expression of PAR2 and nephrin in the kidney were observed at 30 weeks. Administration of GB88 increased blood pressure (BP) and proteinuria. Azilsartan reduced the high BP and the impaired PAR2‐mediated vasorelaxation, but did not restore the increase in urinary protein levels and decreased PAR2 and nephrin protein expression in the kidney. PAR2 activation in the kidney may be associated with maintenance of BP and urinary protein excretion in MetS.

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“…Numerous studies with naturally-occurring polyphenols have shown that a direct blockade targeting podocyte EMT ameliorates podocyte injury and proteinuria [ 23 , 40 ]. In addition, podocyte slit diaphragm has been a therapeutic target of proteinuria [ 5 , 41 ]. This study found that the polymethoxylated flavone tangeretin inhibited EMT process in diabetic podocytes and diabetic mouse kidneys.…”

Section: Discussionmentioning

confidence: 99%

Tangeretin Ameliorates Glucose-Induced Podocyte Injury through Blocking Epithelial to Mesenchymal Transition Caused by Oxidative Stress and Hypoxia

Kang

Kim

et al. 2020

IJMS

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Podocyte injury inevitably results in leakage of proteins from the glomerular filter and is vital in the pathogenesis of diabetic nephropathy (DN). The underlying mechanisms of podocyte injury facilitate finding of new therapeutic targets for DN treatment and prevention. Tangeretin is an O-polymethoxylated flavone present in citrus peels with anti-inflammatory and antioxidant properties. This study investigated the renoprotective effects of tangeretin on epithelial-to-mesenchymal transition-mediated podocyte injury and fibrosis through oxidative stress and hypoxia caused by hyperglycemia. Mouse podocytes were incubated in media containing 33 mM glucose in the absence and presence of 1–20 μM tangeretin for up to 6 days. The in vivo animal model employed db/db mice orally administrated with 10 mg/kg tangeretin for 8 weeks. Non-toxic tangeretin inhibited glucose-induced expression of the mesenchymal markers of N-cadherin and α-smooth muscle actin in podocytes. However, the reduced induction of the epithelial markers of E-cadherin and P-cadherin was restored by tangeretin in diabetic podocytes. Further, tangeretin enhanced the expression of the podocyte slit diaphragm proteins of nephrin and podocin down-regulated by glucose stimulation. The transmission electron microscopic images revealed that foot process effacement and loss of podocytes occurred in diabetic mouse glomeruli. However, oral administration of 10 mg/kg tangeretin reduced urine albumin excretion and improved foot process effacement of diabetic podocytes through inhibiting loss of slit junction and adherenes junction proteins. Glucose enhanced ROS production and HIF-1α induction in podocytes, leading to induction of oxidative stress and hypoxia. Similarly, in diabetic glomeruli reactive oxygen species (ROS) production and HIF-1α induction were observed. Furthermore, hypoxia-evoking cobalt chloride induced epithelial-to-mesenchymal transition (EMT) process and loss of slit diaphragm proteins and junction proteins in podocytes, which was inhibited by treating submicromolar tangeretin. Collectively, these results demonstrate that tangeretin inhibited podocyte injury and fibrosis through blocking podocyte EMT caused by glucose-induced oxidative stress and hypoxia.

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New insight into podocyte slit diaphragm, a therapeutic target of proteinuria

Cited by 90 publications

References 129 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

Activation of protease‐activated receptor 2 is associated with blood pressure regulation and proteinuria reduction in metabolic syndrome

Tangeretin Ameliorates Glucose-Induced Podocyte Injury through Blocking Epithelial to Mesenchymal Transition Caused by Oxidative Stress and Hypoxia

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