scholarly journals Redefining the Role of ADAM17 in Renal Proximal Tubular Cells and Its Implications in an Obese Mouse Model of Pre-Diabetes

2021 ◽  
Vol 22 (23) ◽  
pp. 13093
Author(s):  
Vanesa Palau ◽  
Sofia Villanueva ◽  
Josué Jarrín ◽  
David Benito ◽  
Eva Márquez ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Kidney Injury ◽  
Proximal Tubules ◽  
Obese Mouse ◽  
Glomerular Injury ◽  
Mice Model ◽  
Renal Histology ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular

Acute and chronic kidney lesions induce an increase in A Disintegrin And Metalloproteinase domain 17 (ADAM17) that cleaves several transmembrane proteins related to inflammatory and fibrotic pathways. Our group has demonstrated that renal ADAM17 is upregulated in diabetic mice and its inhibition decreases renal inflammation and fibrosis. The purpose of the present study was to analyze how Adam17 deletion in proximal tubules affects different renal structures in an obese mice model. Tubular Adam17 knockout male mice and their controls were fed a high-fat diet (HFD) for 22 weeks. Glucose tolerance, urinary albumin-to-creatinine ratio, renal histology, and pro-inflammatory and pro-fibrotic markers were evaluated. Results showed that wild-type mice fed an HFD became obese with glucose intolerance and renal histological alterations mimicking a pre-diabetic condition; consequently, greater glomerular size and mesangial expansion were observed. Adam17 tubular deletion improved glucose tolerance and protected animals against glomerular injury and prevented podocyte loss in HFD mice. In addition, HFD mice showed more glomerular macrophages and collagen accumulation, which was prevented by Adam17 deletion. Galectin-3 expression increased in the proximal tubules and glomeruli of HFD mice and ameliorated with Adam17 deletion. In conclusion, Adam17 in proximal tubules influences glucose tolerance and participates in the kidney injury in an obese pre-diabetic murine model. The role of ADAM17 in the tubule impacts on glomerular inflammation and fibrosis.

scholarly journals Canagliflozin protects against cisplatin-induced acute kidney injury by AMPK-mediated autophagy in renal proximal tubular cells

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Cheol Ho Park ◽  
Bin Lee ◽  
Myeonggil Han ◽  
Woo Joong Rhee ◽  
Man Sup Kwak ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Protective Effect ◽  
Kidney Injury ◽  
Proximal Tubular Cells ◽  
Cell Viability Assay ◽  
Tubular Cells ◽  
Compound C ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular

AbstractSodium-glucose cotransporter 2 inhibitors, which are recently introduced as glucose-lowering agents, improve cardiovascular and renal outcomes in patients with diabetes mellitus. These drugs also have beneficial effects in various kidney disease models. However, the effect of SGLT2 inhibitors on cisplatin-induced acute kidney injury (AKI) and their mechanism of action need to be elucidated. In this study, we investigated whether canagliflozin protects against cisplatin-induced AKI, depending on adenosine monophosphate-activated protein kinase (AMPK) activation and following induction of autophagy. In the experiments using the HK-2 cell line, cell viability assay and molecular analysis revealed that canagliflozin protected renal proximal tubular cells from cisplatin, whereas addition of chloroquine or compound C abolished the protective effect of canagliflozin. In the mouse model of cisplatin-induced AKI, canagliflozin protected mice from cisplatin-induced AKI. However, treatment with chloroquine or compound C in addition to administration of cisplatin and canagliflozin eliminated the protective effect of canagliflozin. Collectively, these findings indicate that canagliflozin protects against cisplatin-induced AKI by activating AMPK and autophagy in renal proximal tubular cells.

scholarly journals Overexpression of Nrf2 in Renal Proximal Tubular Cells Stimulates Sodium-Glucose Co-Transporter 2 Expression and Exacerbates Dysglycemia and Kidney Injury in Diabetic Mice

2021 ◽  
Author(s):  
Shuiling Zhao ◽  
Chao-Sheng Lo ◽  
Kana N. Miyata ◽  
Anindya Ghosh ◽  
Xinping Zhao ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Promoter Activity ◽  
Kidney Injury ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Patients With Diabetes ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular ◽  
The Impact

We investigated the impact of nuclear factor erythroid 2-related factor 2 (Nrf2) overexpression in renal proximal tubular cells (RPTCs) on blood glucose, kidney injury and sodium-glucose co-transporter 2 (Sglt2) expression in diabetic Akita <i>Nrf2</i><sup>-/-</sup>/<i>Nrf2<sup>RPTC</sup></i> transgenic (Tg) mice. Immortalized human RPTCs (HK2) stably transfected with plasmid containing the <i>SGLT2</i> promoter, human kidneys from patients with diabetes were also studied. Nrf2 overexpression was associated with increased blood glucose, glomerular filtration rate, urinary albumin-creatinine ratio, tubulointerstitial fibrosis and Sglt2 expression in Akita <i>Nrf2</i><sup>-/-</sup>/<i>Nrf2<sup>RPTC</sup></i> Tg mice compared to their Akita <i>Nrf2</i><sup>-/-</sup> littermates. <i>In vitro</i>, oltipraz or transfection of <i>NRF2</i> cDNA stimulated SGLT2 expression and <i>SGLT2</i> promoter activity in HK2, and these effects were inhibited by trigonelline or <i>NRF2 </i>small interfering RNA. The deletion of the <i>NRF2</i>-<i>responsive element (NRF2-RE)</i> in the <i>SGLT2</i> promoter abolished the stimulatory effect of oltipraz on <i>SGLT2 </i>promoter activity. NRF2 binding to the <i>NRF2</i>-<i>RE</i> of the <i>SGLT2</i> promoter was confirmed by gel mobility shift assay and chromatin immunoprecipitation assays. Kidneys from patients with diabetes exhibited higher levels of NRF2 and SGLT2 in the RPTCs than kidneys from patients without diabetes. These results suggest a link by which NRF2 mediates hyperglycemia-stimulation of SGLT2 expression and exacerbates blood glucose and kidney injury in diabetes.

scholarly journals Evaluation of the Role of Na+/ K+ ATPase Ion Transporters and Na+/K+/ 2Cl and Na+/H+ Exchanger Cotransporters in Nephrons of Periophthalmus Waltoni Using Immunohistochemistry and Histology

2021 ◽  
Author(s):  
Kave Esfandiari ◽  
Mohammad Babaei ◽  
Mina Amiri-Farahani ◽  
Ali Kalantari-Hesari ◽  
Hassan Morovvati
Keyword(s):  
Epithelial Cells ◽  
Kidney Tissue ◽  
Proximal Tubules ◽  
Renal Tubules ◽  
Ion Regulation ◽  
Renal Histology ◽  
Collecting Ducts ◽  
Distal Tubules ◽  
Periophthalmus Waltoni

Abstract Kidneys play an important role in regulating the balance of water and ions in freshwater and seawater fish. However, complex kidney structures impair a comprehensive understanding of kidney function. In this study, in addition to renal histology, Na+/K+/ATPase ion transporter proteins and Na+/K+/2Cl− and NHE3 cotransporters were located in Priophthalmus waltoni kidney tissue to evaluate the ion regulation abilities of epithelial cells in various parts of nephrons. The renal tubules are composed of proximal tubules and distal tubules, followed by collecting tubes and finally collecting ducts. Light microscope immunohistochemistry was utilized to locate Na+/ K+-ATPase along renal tubules and collecting ducts. However, the distribution of the Na+/K+-ATPase immune response varies in different sections. Na+/K+/CL− cotransporter positioning was reported only in collecting tubes and collecting ducts, and proximal tubes and distal tubes did not respond to Na+/K+/Cl− cotransporter immunolocalization. Immunohistochemical response for NHE3 localization was detected only at the apex of epithelial cells of proximal tubules and collecting tubes. The distal tubes showed negative reaction and the collecting ducts showed a weak response to NHE3 safety immunolocalization.

Gentamicin inhibits rat renal cortical homotypic endosomal fusion: role of megalin

1997 ◽  
Vol 272 (1) ◽  
pp. F117-F123 ◽  
Author(s):  
T. G. Hammond ◽  
R. R. Majewski ◽  
J. H. Kaysen ◽  
F. O. Goda ◽  
G. L. Navar ◽  
...  
Keyword(s):  
Damage Mechanism ◽  
Repeat Sequence ◽  
Sequence Motifs ◽  
Polyaspartic Acid ◽  
In Vitro Reconstitution ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular

Megalin, a giant glycoprotein receptor heavily concentrated in the early endosomal pathway of renal proximal tubular cells, binds gentamicin with high affinity and delivers the drug to lysosomes. Utilizing an in vitro reconstitution assay we tested whether gentamicin-induced vacuolation is associated with inhibition of early endosomal fusion, as well as whether megalin plays a role in mediating these effects. Pretreatment of rats with gentamicin inhibited rat renal proximal tubular homotypic endosomal fusion. Administered simultaneously, gentamicin and polymers of polyaspartic acid, which protect against the hemodynamic effects of gentamicin nephrotoxicity, had no net effect on fusion. Polyaspartic acid alone had no effect on fusion. Antisera to the tail of the megalin/gentamicin receptor inhibited fusion, whereas non-specific controls had no effect. Peptides matching homologous NPXY repeat sequence motifs in the cytosolic tail stimulated endosomal fusion, whereas reverse sequence control peptides had no effect. These data suggest that gentamicin inhibition of endosomal fusion in the renal proximal tubule is a damage mechanism mediated by specific peptide sequences in the cytosolic tail of the giant gentamicin-binding receptor megalin and that receptors can effect the fusion properties of membranes in which they reside.

scholarly journals Regenerative Role of Stem Cell-Derived Extracellular Vesicles in Acute Kidney Injury

Nephron ◽  
2020 ◽  
Vol 144 (12) ◽  
pp. 638-643
Author(s):  
Davide Medica ◽  
Sergio Dellepiane ◽  
Vincenzo Cantaluppi
Keyword(s):  
Acute Kidney Injury ◽  
Clinical Trials ◽  
Extracellular Vesicles ◽  
Therapeutic Option ◽  
Kidney Injury ◽  
Glomerular Injury ◽  
Paracrine Factors ◽  
Short And Long Term

Acute kidney injury (AKI) is a frequent complication of hospital admission and worsens short- and long-term patients’ prognosis. Currently, AKI treatment remains supportive and no therapy has proven significant benefit in clinical trials. Stem cells (SCs) are a promising therapeutic option, but their translation to the clinical setting is limited by the risk of rejection or aberrant differentiation. Numerous studies have shown how SC effects are mediated by paracrine factors such as extracellular vesicles (EVs). In this review, we describe the preclinical evidence about EV efficacy in acute tubular and glomerular injury and the recently generated clinical data.

scholarly journals Long Non-coding RNA H19 Augments Hypoxia/Reoxygenation-Induced Renal Tubular Epithelial Cell Apoptosis and Injury by the miR-130a/BCL2L11 Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuan Yuan ◽  
Xiaoling Li ◽  
Yudong Chu ◽  
Gongjie Ye ◽  
Lei Yang ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Kidney Injury ◽  
Tubular Epithelial Cell ◽  
Promote Cell Proliferation ◽  
Proliferation And Apoptosis ◽  
Non Coding Rnas ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular ◽  
Hypoxia Reoxygenation

Acute kidney injury (AKI) is a severe kidney disease defined by partial or abrupt loss of renal function. Emerging evidence indicates that non-coding RNAs (ncRNAs), particularly long non-coding RNAs (lncRNAs), function as essential regulators in AKI development. Here we aimed to explore the underlying molecular mechanism of the lncRNA H19/miR-130a axis for the regulation of inflammation, proliferation, and apoptosis in kidney epithelial cells. Human renal proximal tubular cells (HK-2) were induced by hypoxia/reoxygenation to replicate the AKI modelin vitro. After treatment, the effects of LncRNA H19 and miR-130a on proliferation and apoptosis of HK-2 cells were investigated by CCK-8 and flow cytometry. Meanwhile, the expressions of LncRNA H19, miR-130a, and inflammatory cytokines were detected by qRT-PCR, western blot, and ELISA assays. The results showed that downregulation of LncRNA H19 could promote cell proliferation, inhibit cell apoptosis, and suppress multiple inflammatory cytokine expressions in HK-2 cells by modulating the miR-130a/BCL2L11 pathway. Taken together, our findings indicated that LncRNA H19 and miR-130a might represent novel therapeutic targets and early diagnostic biomarkers for the treatment of AKI.

IL-1 receptor signaling in podocytes limits susceptibility to glomerular damage

2021 ◽  
Author(s):  
Jiafa Ren ◽  
Xiaohan Lu ◽  
Gentzon Hall ◽  
Jamie R Privratsky ◽  
Matthew J Robson ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Protective Role ◽  
Glomerular Disease ◽  
Wild Type ◽  
Glomerular Injury ◽  
Podocyte Injury ◽  
Akt Activation ◽  
Injury Models ◽  
Dependent Signaling Pathway

IL-1 receptor (IL-1R1) activation triggers a proinflammatory signaling cascade that can exacerbate kidney injury. However, the functions of the podocyte IL-1R1 in glomerular disease remain unclear. To study the role of IL-1R1 signaling in podocytes, we selectively ablated the podocyte IL-1R1 in mice (PKO). We then subjected PKO mice and wild-type (WT) controls to 2 glomerular injury models: nephrotoxic serum (NTS)- and adriamycin (ADR)-induced nephropathy. Surprisingly, we found IL-1R1 activation in podocytes limited albuminuria and podocyte injury during NTS- and ADR-induced nephropathy. Moreover, deletion of IL-1R1 in podocytes drove podocyte apoptosis and glomerular injury through diminishing Akt activation. Activation of Akt signaling abrogated the differences in albuminuria and podocyte injury between WT and PKO mice during NTS. Thus, IL-1R1 signaling in podocytes limits susceptibility to glomerular injury via an Akt-dependent signaling pathway. These data identify an unexpected protective role for IL-1R1 signaling in podocytes in the pathogenesis of glomerular disease.

Sign in / Sign up

Export Citation Format

Share Document