Modes of podocyte death in diabetic kidney disease: an update

Jiang, Anni; Song, Anni; Zhang, Chun

doi:10.1007/s40620-022-01269-1

Cited by 23 publications

(16 citation statements)

References 109 publications

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“…Additionally, differentiated podocytes possess other inherent obstacles to mitosis, weaken their proliferative response and impeding recovery from injury. While under stress condition, they tend to develop irregularly shaped nuclei, abnormal mitotic spindles, and in cytokinesis, ultimately leading to aneuploidy (43). Mature podocytes exit the cell cycle, as evidenced by the lower expression of the proliferation markers (i.e., Ki67, PCNA, and Cyclin B1) (13,14).…”

Section: Discussionmentioning

confidence: 99%

The effect of METTL3 on MDM2 impairs cell cycle homeostasis in podocytes during diabetic kidney disease

Wu,

Yu,

Yang

et al. 2024

Preprint

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N6-Methyladenosine (m6A) methylation is involved in various pathological processes. Our previous study found abnormal expression of the methyltransferases enzyme METTL3 in aging kidney tissues, resulting in renal fibrosis and aging. In this study, we aim to elucidate its regulatory mechanisms in diabetic kidney disease (DKD) by establishing a conditional METTL3 knockout model. We observed elevated m6A levels in the kidney of mice with type I diabetes and in cultured mouse podocytes exposed to advanced glycation end-products (AGEs), which could be attributed to increased METTL3 expression. Podocyte-specific METTL3 knockdown significantly mitigated podocyte injury in streptozotocin (STZ)-induced diabetic mice, leading to reduced urine albuminuria and renal pathology. Mechanistically, METTL3 induced abnormal m6A modification of MDM2, triggering subsequent degradation in an IGF2BP2 dependent manner. Consequently, this abnormal m6A regulation induces increased MDM2 expression, activates the Notch signaling pathway, induced podocyte cell cycle re-entry under diabetic conditions, releases inflammatory factors, and induces dedifferentiation of podocytes. Thus, METTL3-mediated aberrant m6A modification plays a pivotal role in podocytes under diabetic conditions. Targeting m6A via METTL3 is a potentially effective strategy for DKD treatment.

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Section: Discussionmentioning

confidence: 99%

The effect of METTL3 on MDM2 impairs cell cycle homeostasis in podocytes during diabetic kidney disease

Wu,

Yu,

Yang

et al. 2024

Preprint

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“…The main characteristics of DN are persistent proteinuria, elevated creatinine levels and decreased glomerular filtration rate. Pathologically, podocyte injury, glomerulosclerosis, glomerular basement membrane thickening, interstitial fibrosis and tubular atrophy mainly contribute to the development of DN [ 5 ]. Podocyte insulin resistance is a main cause of podocyte injury, playing a crucial role in contributing to albuminuria in early DN [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Diagnostic Value of the Combined Measurement of Serum HCY and NRG4 in Type 2 Diabetes Mellitus with Early Complicating Diabetic Nephropathy

Ding

Yang

Zheng

et al. 2023

JPM

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Purpose: This study aimed to investigate the value of combined detection of HCY and NRG4 in the diagnosis of early diabetic kidney disease (DKD) and to explore the association between the ratio of HCY/NRG4 and DKD. Methods: A total of 140 diabetic patients and 43 healthy people were prospectively enrolled. The plasma HCY level, NRG4 level and HCY/NRG4 of them were measured to compare their differences and analyze the correlation with DKD. The independent influencing factors of patients with DKD were screened, and the nomograph of DKD occurrence was constructed. Results: The levels of HCY and HCY/NRG4 in diabetic patients were significantly increased, while the level of NRG4 was significantly decreased (p < 0.01). The AUCs of HCY/NRG4 predicted for DKD were 0.961. HCY/NRG4 and the course of DM were independent risk factors for DKD. A predictive nomograph of DKD was constructed, and decision curve analysis (DCA) showed good clinical application value. HCY/NRG4 was positively correlated with Scr, UACR, TG, UA, BUN, TCHOL and LDL and negatively correlated with eGFR and HDL (p < 0.05). Conclusions: The level of HCY and NRG4 is closely related to the severity of DM, and combined detection of HCY/NRG4 can identify patients with DKD at an early stage.

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“…DKD is characterized by progressive albuminuria, which occurs following the destruction of the glomerular filtration barrier 1–3 . As one of the key structural components of this barrier, podocytes play a crucial role in maintaining glomerular permselectivity 4,5 . In diabetes, podocytes are subjected to injury through various pathogenic cues, including hyperglycaemia, 6 oxidative stress 7 and inflammation 8 …”

Section: Introductionmentioning

confidence: 99%

Dihydroxyacetone phosphate accumulation leads to podocyte pyroptosis in diabetic kidney disease

Zhang,

Hu,

Luo

et al. 2023

J Cellular Molecular Medi

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Diabetic kidney disease (DKD) can lead to accumulation of glucose upstream metabolites due to dysfunctional glycolysis. But the effects of accumulated glycolysis metabolites on podocytes in DKD remain unknown. The present study examined the effect of dihydroxyacetone phosphate (DHAP) on high glucose induced podocyte pyroptosis. By metabolomics, levels of DHAP, GAP, glucose‐6‐phosphate and fructose 1, 6‐bisphosphate were significantly increased in glomeruli of db/db mice. Furthermore, the expression of LDHA and PKM2 were decreased. mRNA sequencing showed upregulation of pyroptosis‐related genes (Nlrp3, Casp1, etc.). Targeted metabolomics demonstrated higher level of DHAP in HG‐treated podocytes. In vitro, ALDOB expression in HG‐treated podocytes was significantly increased. siALDOB‐transfected podocytes showed less DHAP level, mTORC1 activation, reactive oxygen species (ROS) production, and pyroptosis, while overexpression of ALDOB had opposite effects. Furthermore, GAP had no effect on mTORC1 activation, and mTORC1 inhibitor rapamycin alleviated ROS production and pyroptosis in HG‐stimulated podocytes. Our findings demonstrate that DHAP represents a critical metabolic product for pyroptosis in HG‐stimulated podocytes through regulation of mTORC1 pathway. In addition, the results provide evidence that podocyte injury in DKD may be treated by reducing DHAP.

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Modes of podocyte death in diabetic kidney disease: an update

Cited by 23 publications

References 109 publications

The effect of METTL3 on MDM2 impairs cell cycle homeostasis in podocytes during diabetic kidney disease

The effect of METTL3 on MDM2 impairs cell cycle homeostasis in podocytes during diabetic kidney disease

Diagnostic Value of the Combined Measurement of Serum HCY and NRG4 in Type 2 Diabetes Mellitus with Early Complicating Diabetic Nephropathy

Dihydroxyacetone phosphate accumulation leads to podocyte pyroptosis in diabetic kidney disease

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