Suppressed ER‐associated degradation by intraglomerular cross talk between mesangial cells and podocytes causes podocyte injury in diabetic kidney disease

Fujimoto, Daisuke; Kuwabara, Tomohiko; Hata, Yusuke; Umemoto, Shuro; Kanki, Tomoko; Nishiguchi, Yoshihiko; Mizumoto, Teruhiko; Hayata, Manabu; Kakizoe, Yutaka; Yokoyama, Izumi; Takahashi, Satoru; Mukoyama, Masashi

doi:10.1096/fj.202000078rr

Cited by 17 publications

(16 citation statements)

References 45 publications

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“…Indeed, expressions of ER stress-and UPR-related genes are significantly increased and closely related with kidney function in CKD patients [18]. Moreover, this observation has been confirmed in a number of preclinical studies [20,27,[48][49][50]. Therefore, UPR and ERAD are implicated in the pathogenesis of kidney diseases including CKD, emerging as novel targets for CKD management [26-28, 51, 52].…”

Section: Discussionmentioning

confidence: 95%

“…ER-associated degradation (ERAD), served as a critical branch of ER stress, is subsequently triggered to degrade these improperly folded proteins, thereby maintaining cellular homeostasis [25]. Considering its critical physiological significance, ERAD is implicated in the pathogenesis and development of diverse diseases including kidney diseases [26][27][28]. Hence, we speculate that CKD disturbs normal processing of Klotho protein, results in aggregation of improperly folded Klotho in ER, and consequently accelerates Klotho protein degradation via the ERAD pathway, thus contributing at least partially to Klotho deficiency.…”

Section: Introductionmentioning

confidence: 99%

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Abnormally decreased renal Klotho is linked to endoplasmic reticulum-associated degradation in mice

Li¹,

Kong²,

Liu³

et al. 2022

Int. J. Med. Sci.

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Aim: Endoplasmic reticulum-associated degradation (ERAD), which involves degradation of improperly folded proteins retained in the ER, is implicated in various diseases including chronic kidney disease. This study is aimed to determine the role of ERAD in Klotho deficiency of mice and human kidney tubular epithelial cells (HK-2) with renal interstitial fibrosis (RIF). Methods: Following establishment of a mouse RIF model by unilateral ureteral obstruction (UUO), a specific ERAD inhibitor, Eeyarestatin I (EerI), was administered to experimental animals by intraperitoneal injection. Serum and kidney samples were collected for analysis 10 days after operation. Soluble Klotho levels were measured by enzyme-linked immunosorbent assay, while the degree of kidney injury was assessed by renal histopathology. Renal Klotho expression was determined by quantitative real-time PCR, immunohistochemical and western blotting analyses. ERAD and unfolded protein response (UPR) were evaluated by detecting associated components such as Derlin-1, glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4) and protein disulfide isomerase (PDI). HK-2 cells were exposed to transforming growth factor (TGF)-β1 with or without EerI, and expressions of related proteins including Klotho, Derlin-1, GRP78, ATF4 and PDI were determined by western blotting analyses. Results: UUO induced severe kidney injuries and RIF. Klotho expression in both serum and kidney tissue was obviously downregulated, while Derlin-1 was notably upregulated, indicating that ERAD was activated to potentially degrade improperly folded Klotho protein in this model. Intriguingly, treatment with EerI led to significantly increased Klotho expression, especially soluble (functional) Klotho. Furthermore, specific inhibition of ERAD increased expression of GRP78, ATF4 and PDI compared with the UUO group. The consistent results in vitro were also obtained in TGF-β1-treated HK-2 cells exposed to EerI. These observations suggest that UPR was remarkably enhanced in the presence of ERAD inhibition and compensated for excess improperly folded proteins, subsequently contributing to the additional production of mature Klotho protein. Conclusion:ERAD is involved in Klotho deficiency in RIF and its specific inhibition significantly promoted Klotho expression, possibly through enhanced UPR. This may represent a novel regulatory mechanism and new therapeutic target for reversing Klotho deficiency.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Abnormally decreased renal Klotho is linked to endoplasmic reticulum-associated degradation in mice

Li¹,

Kong²,

Liu³

et al. 2022

Int. J. Med. Sci.

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“…Culturing MCs in high glucose and transferring the medium to podocytes led to inhibition of the endoplasmic-reticulum-associated protein degradation pathway (ERAD) and podocyte injury. In diabetic mice inhibition of ERAD resulted in increased albuminuria, podocyte apoptosis and reduced nephrin expression ( 186 ). The identities of the specific molecules produced by the MCs leading to podocyte damage are unknown.…”

Section: Mesangial-podocyte Crosstalkmentioning

confidence: 99%

The Glomerulus According to the Mesangium

2022

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The glomerulus is the functional unit for filtration of blood and formation of primary urine. This intricate structure is composed of the endothelium with its glycocalyx facing the blood, the glomerular basement membrane and the podocytes facing the urinary space of Bowman's capsule. The mesangial cells are the central hub connecting and supporting all these structures. The components as a unit ensure a high permselectivity hindering large plasma proteins from passing into the urine while readily filtering water and small solutes. There has been a long-standing interest and discussion regarding the functional contribution of the different cellular components but the mesangial cells have been somewhat overlooked in this context. The mesangium is situated in close proximity to all other cellular components of the glomerulus and should be considered important in pathophysiological events leading to glomerular disease. This review will highlight the role of the mesangium in both glomerular function and intra-glomerular crosstalk. It also aims to explain the role of the mesangium as a central component involved in disease onset and progression as well as signaling to maintain the functions of other glomerular cells to uphold permselectivity and glomerular health.

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“…(91). The diabetic podocyte produces excessive VEGF in the setting of low endothelial NO and stimulates growth and proliferation of mesangial and endothelial cells, leading to increased extracellular matrix accumulation, hyperfiltration, and proteinuria (92). A recent research has shown that an intraglomerular crosstalk between mesangial cells and podocytes can inhibit physiological endoplasmic reticulum stress-associated degradation (ERAD) and suppress the phosphorylation of nephrin in podocytes, which thereby lead to podocyte injury under diabetic conditions (92).…”

Section: Gmc-gec Integrin αVβ8mentioning

confidence: 99%

Single Cell Transcriptome Helps Better Understanding Crosstalk in Diabetic Kidney Disease

Ren

et al. 2021

Front. Med.

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Years of research revealed that crosstalk extensively existed among kidney cells, cell factors and metabolites and played an important role in the development of diabetic kidney disease (DKD). In the last few years, single-cell RNA sequencing (scRNA-seq) technology provided new insight into cellular heterogeneity and genetic susceptibility regarding DKD at cell-specific level. The studies based on scRNA-seq enable a much deeper understanding of cell-specific processes such as interaction between cells. In this paper, we aim to review recent progress in single cell transcriptomic analyses of DKD, particularly highlighting on intra- or extra-glomerular cell crosstalk, cellular targets and potential therapeutic strategies for DKD.

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Suppressed ER‐associated degradation by intraglomerular cross talk between mesangial cells and podocytes causes podocyte injury in diabetic kidney disease

Cited by 17 publications

References 45 publications

Abnormally decreased renal Klotho is linked to endoplasmic reticulum-associated degradation in mice

Abnormally decreased renal Klotho is linked to endoplasmic reticulum-associated degradation in mice

The Glomerulus According to the Mesangium

Single Cell Transcriptome Helps Better Understanding Crosstalk in Diabetic Kidney Disease

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