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1.
Int J Med Sci ; 19(2): 321-330, 2022.
Article in English | MEDLINE | ID: mdl-35165517

ABSTRACT

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)-ß1 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-ß1-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.


Subject(s)
Endoplasmic Reticulum-Associated Degradation/genetics , Kidney/pathology , Klotho Proteins/deficiency , Nephritis, Interstitial/enzymology , Ureteral Obstruction/enzymology , Animals , Disease Models, Animal , Fibrosis , Humans , Hydrazones/administration & dosage , Hydroxyurea/administration & dosage , Hydroxyurea/analogs & derivatives , Injections, Intraperitoneal , Kidney Tubules/cytology , Klotho Proteins/drug effects , Mice
2.
Cell Rep ; 38(7): 110392, 2022 02 15.
Article in English | MEDLINE | ID: mdl-35172146

ABSTRACT

The composition and origin of extrinsic cues required for hematopoietic stem cell (HSC) maintenance are incompletely understood. Here we identify renal Klotho and inorganic phosphate (Pi) as extrinsic factors that antagonistically regulate HSC maintenance in the bone marrow (BM). Disruption of the Klotho-Pi axis by renal Klotho deficiency or Pi excess causes Pi overload in the BM niche and Pi retention in HSCs, leading to alteration of HSC maintenance. Mechanistically, Pi retention is mediated by soluble carrier family 20 member 1 (SLC20A1) and sensed by diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2) to enhance Akt activation, which then upregulates SLC20A1 to aggravate Pi retention and augments GATA2 activity to drive the expansion and megakaryocyte/myeloid-biased differentiation of HSCs. However, kidney-secreted soluble Klotho directly maintains HSC pool size and differentiation by restraining SLC20A1-mediated Pi absorption of HSCs. These findings uncover a regulatory role of the Klotho-Pi axis orchestrated by the kidneys in BM HSC maintenance.


Subject(s)
Hematopoietic Stem Cells/cytology , Kidney/metabolism , Klotho Proteins/metabolism , Phosphates/metabolism , Animals , Bone Marrow Cells/metabolism , Cell Differentiation , GATA2 Transcription Factor/metabolism , Hematopoietic Stem Cells/metabolism , Homeostasis , Klotho Proteins/deficiency , Mice, Inbred C57BL , Phosphotransferases (Phosphate Group Acceptor)/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Sodium-Phosphate Cotransporter Proteins, Type III/metabolism , Solubility
3.
Clin J Am Soc Nephrol ; 16(1): 162-176, 2020 12 31.
Article in English | MEDLINE | ID: mdl-32699047

ABSTRACT

αKlotho (called Klotho here) is a membrane protein that serves as the coreceptor for the circulating hormone fibroblast growth factor 23 (FGF23). Klotho is also cleaved and released as a circulating substance originating primarily from the kidney and exerts a myriad of housekeeping functions in just about every organ. The vital role of Klotho is shown by the multiorgan failure with genetic deletion in rodents, with certain features reminiscent of human disease. The most common causes of systemic Klotho deficiency are AKI and CKD. Preclinical data on Klotho biology have advanced considerably and demonstrated its potential diagnostic and therapeutic value; however, multiple knowledge gaps exist in the regulation of Klotho expression, release, and metabolism; its target organs; and mechanisms of action. In the translational and clinical fronts, progress has been more modest. Nonetheless, Klotho has potential clinical applications in the diagnosis of AKI and CKD, in prognosis of progression and extrarenal complications, and finally, as replacement therapy for systemic Klotho deficiency. The overall effect of Klotho in clinical nephrology requires further technical advances and additional large prospective human studies.


Subject(s)
Acute Kidney Injury/metabolism , Cardiovascular Diseases/metabolism , Klotho Proteins/metabolism , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/metabolism , Acute Kidney Injury/therapy , Animals , Biomarkers/metabolism , Cell Physiological Phenomena , Gene Expression/drug effects , Genetic Therapy , Humans , Klotho Proteins/blood , Klotho Proteins/deficiency , Klotho Proteins/genetics , Minerals/metabolism
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