Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress

Delitsikou, Vasiliki; Jarad, George; Rajaram, R; Ino, Frédérique; Rutkowski, Joseph M.; Chen, Ci Di; Santos, Célio X.C.; Scherer, Philipp E.; Abraham, Carmela R.; Shah, Ajay M.; Féraille, Eric; Miner, Jeffrey H.; Seigneux, Sophie de

doi:10.1096/fj.201900893r

Cited by 21 publications

(15 citation statements)

References 72 publications

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“…A minority of renal tubular cells take this transition further and migrate to the interstitium where, along with existing interstitial fibroblasts, they contribute directly to the production of extracellular matrix and fibrosis. Albumin exposure also directly, via an epigenetic mechanism, reduces Klotho expression in proximal tubular cells, which is believed to contribute to hyperphosphataemia, higher levels of fibroblast growth factor-23, and lower levels of circulating Klotho [34, 35]. This may, in part, explain the importance of albuminuria as a cardiovascular risk factor; a link demonstrated by the finding that, independent of changes in other biomarkers, albuminuria lowering explained 36% of the beneficial effect of canagliflozin on cardiovascular events [36].…”

Section: Proteinuria and Progressive Kidney Diseasementioning

confidence: 99%

From Proteinuria to Fibrosis: An Update on Pathophysiology and Treatment Options

Sharma

Smyth

2021

Kidney Blood Press Res

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Background: Proteinuria is a key biomarker in nephrology. It is central to diagnosis and risk assessment and the primary target of many important therapies. Etiologies resulting in pathological proteinuria include congenital and acquired disorders, as well as both glomerular (immune/non-immune mediated) and tubular defects. Summary: Untreated proteinuria is strongly linked to progressive loss of kidney function and kidney failure. Excess protein reaching the renal tubules is ordinarily resorbed by the tubular epithelium. However, when these mechanisms are overwhelmed, a variety of inflammatory and fibrotic pathways are activated, causing both interstitial fibrosis and glomerulosclerosis. Nevertheless, the specific mechanisms underlying this are complex and remain incompletely understood. Recently, a number of treatments, in addition to angiotensin system blockade, have been shown to effectively slow the progression of proteinuric chronic kidney disease. However, additional therapies are clearly needed. Key message: This review provides an update on the pathophysiology of proteinuria, the pathways leading to fibrosis, and an overview of current and emerging therapies.

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Section: Proteinuria and Progressive Kidney Diseasementioning

confidence: 99%

From Proteinuria to Fibrosis: An Update on Pathophysiology and Treatment Options

Sharma

Smyth

2021

Kidney Blood Press Res

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“…Particularly, activating transcription factor 3 (ATF3), a potential neuronal marker under pathology, was activated on small nociceptors in concert with skin denervation [ 10 ], suggesting that ATF3 is a critical marker in addition to noxious transduction by IENF. ATF3 has also been suggested to be a marker of ER stress, and it negatively affects ER stress in obesity-related diabetes [ 11 , 12 ] and in renal tissue failure [ 13 ] due to obesity-lipotoxicity-induced ATF3 activation and ER stress. ATF3 has paradoxical regulatory roles; ATF3 deficiency suppresses transplant rejection by ameliorating the inflammatory response [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic loss-of-function of activating transcription factor 3 but not C-type lectin member 5A prevents diabetic peripheral neuropathy

Kan

Chang

et al. 2021

Laboratory Investigation

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We investigated the mediating roles of activating transcription factor 3 (ATF3), an injury marker, or C-type lectin member 5A (CLEC5A), an inflammatory response molecule, in the induction of endoplasmic reticulum (ER) stress and neuroinflammation in diabetic peripheral neuropathy in ATF3 and CLEC5A genetic knockout (aft3−/− and clec5a−/−, respectively) mice. ATF3 was expressed intranuclearly and was upregulated in mice with diabetic peripheral neuropathy (DN) and clec5a−/− mice. The DN and clec5a−/− groups also exhibited neuropathic behavior, but not in the aft3−/− group. The upregulation profiles of cytoplasmic polyadenylation element-binding protein, a protein translation–regulating molecule, and the ER stress-related molecules of inositol-requiring enzyme 1α and phosphorylated eukaryotic initiation factor 2α in the DN and clec5a−/− groups were correlated with neuropathic behavior. Ultrastructural evidence confirmed ER stress induction and neuroinflammation, including microglial enlargement and proinflammatory cytokine release, in the DN and clec5a−/− mice. By contrast, the induction of ER stress and neuroinflammation did not occur in the aft3−/− mice. Furthermore, the mRNA of reactive oxygen species–removing enzymes such as superoxide dismutase, heme oxygenase-1, and catalase were downregulated in the DN and clec5a−/− groups but were not changed in the aft3−/− group. Taken together, the results indicate that intraneuronal ATF3, but not CLEC5A, mediates the induction of ER stress and neuroinflammation associated with diabetic neuropathy.

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“…A recent study by Delitsikou et al demonstrated an association between ER stress activation and reduced Klotho protein levels, and specific inhibition of ER stress restored Klotho protein expression without changing klotho mRNA levels in a proteinuria CKD model [21]. This study was the first to reveal that enhanced Klotho degradation was associated with a loss of Klotho expression, but the exact mechanism remained to be elucidated.…”

Section: Discussionmentioning

confidence: 60%

“…We previously observed that rats with unilateral ureter obstruction (UUO) induced-renal interstitial fibrosis (RIF) featured both ER stress ignition and Klotho loss, and Klotho replacement treatment repressed renal ER stress and improved their kidney function [20]. Furthermore, a recent study demonstrated that inhibition of ER stress rescued Klotho protein downregulation in mice with proteinuria CKD [21], suggesting a close link between ER stress and Klotho expression [22]. Persistent stress in CKD contributes to the continuous deposition of misfolded or unfolded proteins in the ER [23].…”

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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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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Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress

Cited by 21 publications

References 72 publications

From Proteinuria to Fibrosis: An Update on Pathophysiology and Treatment Options

From Proteinuria to Fibrosis: An Update on Pathophysiology and Treatment Options

Genetic loss-of-function of activating transcription factor 3 but not C-type lectin member 5A prevents diabetic peripheral neuropathy

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

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