Reduced urinary corin levels in patients with chronic kidney disease

2013 ◽  
Vol 124 (12) ◽  
pp. 709-717 ◽  
Author(s):  
Chaodong Fang ◽  
Lei Shen ◽  
Liang Dong ◽  
Meng Liu ◽  
Sensen Shi ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Human Urine ◽  
Animal Studies ◽  
Kidney Tissue ◽  
Renal Tubules ◽  
Tissue Samples ◽  
Protein Levels ◽  
Normal Individuals ◽  
Renal Tubular

Corin is a cardiac protease that regulates BP (blood pressure) by activating natriuretic peptides. Recent animal studies identified corin expression in the kidney where it may regulate renal function. In the present study, we tested the hypothesis that corin may be present in human urine and that urinary corin levels may be altered in patients with kidney disease. We obtained urine and kidney tissue samples from normal individuals and CKD (chronic kidney disease) patients. Using ELISA, we detected corin protein in human urine. In normal individuals, urinary corin levels did not correlate with that of plasma, indicating that urinary corin is probably of kidney origin. Compared with normal controls, CKD patients had markedly reduced urinary corin levels and this reduction correlated with disease severity. By immunostaining, human corin protein was identified on the epithelial cell surface in renal tubules. The renal corin mRNA and protein levels were significantly lower in CKD patients than non-CKD controls. The results indicate that renal tubular corin may be shed into urine and that urinary and renal corin levels were reduced in CKD patients. These data suggest that reduced corin levels in the kidney may reflect the underlying pathology in CKD.

scholarly journals Permissive effect of GSK3β on profibrogenic plasticity of renal tubular cells in progressive chronic kidney disease

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Bohan Chen ◽  
Pei Wang ◽  
Xianhui Liang ◽  
Chunming Jiang ◽  
Yan Ge ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Binding Protein ◽  
Renal Tubules ◽  
Genetic Ablation ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Renal Fibrogenesis ◽  
Tgf Β1

AbstractRenal tubular epithelial cells (TECs) play a key role in renal fibrogenesis. After persistent injuries that are beyond self-healing capacity, TECs will dedifferentiate, undergo growth arrest, convert to profibrogenic phenotypes, and resort to maladaptive plasticity that ultimately results in renal fibrosis. Evidence suggests that glycogen synthase kinase (GSK) 3β is centrally implicated in kidney injury. However, its role in renal fibrogenesis is obscure. Analysis of publicly available kidney transcriptome database demonstrated that patients with progressive chronic kidney disease (CKD) exhibited GSK3β overexpression in renal tubulointerstitium, in which the predefined hallmark gene sets implicated in fibrogenesis were remarkably enriched. In vitro, TGF-β1 treatment augmented GSK3β expression in TECs, concomitant with dedifferentiation, cell cycle arrest at G2/M phase, excessive accumulation of extracellular matrix, and overproduction of profibrotic cytokines like PAI-1 and CTGF. All these profibrogenic phenotypes were largely abrogated by GSK3β inhibitors or by ectopic expression of a dominant-negative mutant of GSK3β but reinforced in cells expressing the constitutively active mutant of GSK3β. Mechanistically, GSK3β suppressed, whereas inhibiting GSK3β facilitated, the activity of cAMP response element-binding protein (CREB), which competes for CREB-binding protein, a transcriptional coactivator essential for TGF-β1/Smad signaling pathway to drive TECs profibrogenic plasticity. In vivo, in mice with folic acid-induced progressive CKD, targeting of GSK3β in renal tubules via genetic ablation or by microdose lithium mitigated the profibrogenic plasticity of TEC, concomitant with attenuated interstitial fibrosis and tubular atrophy. Collectively, GSK3β is likely a pragmatic therapeutic target for averting profibrogenic plasticity of TECs and improving renal fibrosis.

scholarly journals Expression correlation attenuates within and between key signaling pathways in chronic kidney disease

2020 ◽  
Vol 13 (S9) ◽  
Author(s):  
Hui Yu ◽  
Danqian Chen ◽  
Olufunmilola Oyebamiji ◽  
Ying-Yong Zhao ◽  
Yan Guo
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Signaling Pathways ◽  
Human Subjects ◽  
Kidney Tissue ◽  
Ckd Progression ◽  
Tissue Samples ◽  
Expression Correlation ◽  
Differential Coexpression ◽  
Differential Coexpression Analysis

Abstract Background Compared to the conventional differential expression approach, differential coexpression analysis represents a different yet complementary perspective into diseased transcriptomes. In particular, global loss of transcriptome correlation was previously observed in aging mice, and a most recent study found genetic and environmental perturbations on human subjects tended to cause universal attenuation of transcriptome coherence. While methodological progresses surrounding differential coexpression have helped with research on several human diseases, there has not been an investigation of coexpression disruptions in chronic kidney disease (CKD) yet. Methods RNA-seq was performed on total RNAs of kidney tissue samples from 140 CKD patients. A combination of differential coexpression methods were employed to analyze the transcriptome transition in CKD from the early, mild phase to the late, severe kidney damage phase. Results We discovered a global expression correlation attenuation in CKD progression, with pathway Regulation of nuclear SMAD2/3 signaling demonstrating the most remarkable intra-pathway correlation rewiring. Moreover, the pathway Signaling events mediated by focal adhesion kinase displayed significantly weakened crosstalk with seven pathways, including Regulation of nuclear SMAD2/3 signaling. Well-known relevant genes, such as ACTN4, were characterized with widespread correlation disassociation with partners from a wide array of signaling pathways. Conclusions Altogether, our analysis reported a global expression correlation attenuation within and between key signaling pathways in chronic kidney disease, and presented a list of vanishing hub genes and disrupted correlations within and between key signaling pathways, illuminating on the pathophysiological mechanisms of CKD progression.

scholarly journals Sugar or Fat? Renal Tubular Metabolism Reviewed in Health and Disease

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1580
Author(s):  
Leslie S. Gewin
Keyword(s):  
Chronic Kidney Disease ◽  
Fatty Acid ◽  
Kidney Disease ◽  
Fatty Acid Oxidation ◽  
Kidney Injury ◽  
Proximal Tubules ◽  
Acid Oxidation ◽  
Renal Tubules ◽  
Solute Movement ◽  
Renal Tubular

The kidney is a highly metabolically active organ that relies on specialized epithelial cells comprising the renal tubules to reabsorb most of the filtered water and solutes. Most of this reabsorption is mediated by the proximal tubules, and high amounts of energy are needed to facilitate solute movement. Thus, proximal tubules use fatty acid oxidation, which generates more adenosine triphosphate (ATP) than glucose metabolism, as its preferred metabolic pathway. After kidney injury, metabolism is altered, leading to decreased fatty acid oxidation and increased lactic acid generation. This review discusses how metabolism differs between the proximal and more distal tubular segments of the healthy nephron. In addition, metabolic changes in acute kidney injury and chronic kidney disease are discussed, as well as how these changes in metabolism may impact tubule repair and chronic kidney disease progression.

Tubular cell-enriched subpopulation of primary renal cells improves survival and augments kidney function in rodent model of chronic kidney disease

2010 ◽  
Vol 299 (5) ◽  
pp. F1026-F1039 ◽  
Author(s):  
Rusty Kelley ◽  
Eric S. Werdin ◽  
Andrew T. Bruce ◽  
Sumana Choudhury ◽  
Shay M. Wallace ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Kidney Function ◽  
Transforming Growth Factor ◽  
Kidney Tissue ◽  
Tubular Cell ◽  
Acute Injury ◽  
Treatment Modalities ◽  
Histological Evaluation ◽  
Renal Cells

Established chronic kidney disease (CKD) may be identified by severely impaired renal filtration that ultimately leads to the need for dialysis or kidney transplant. Dialysis addresses only some of the sequelae of CKD, and a significant gap persists between patients needing transplant and available organs, providing impetus for development of new CKD treatment modalities. Some postulate that CKD develops from a progressive imbalance between tissue damage and the kidney's intrinsic repair and regeneration processes. In this study we evaluated the effect of kidney cells, delivered orthotopically by intraparenchymal injection to rodents 4–7 wk after CKD was established by two-step 5/6 renal mass reduction (NX), on the regeneration of kidney function and architecture as assessed by physiological, tissue, and molecular markers. A proof of concept for the model, cell delivery, and systemic effect was demonstrated with a heterogeneous population of renal cells (UNFX) that contained cells from all major compartments of the kidney. Tubular cells are known contributors to kidney regeneration in situ following acute injury. Initially tested as a control, a tubular cell-enriched subpopulation of UNFX (B2) surprisingly outperformed UNFX. Two independent studies (3 and 6 mo in duration) with B2 confirmed that B2 significantly extended survival and improved renal filtration (serum creatinine and blood urea nitrogen). The specificity of B2 effects was verified by direct comparison to cell-free vehicle controls and an equivalent dose of non-B2 cells. Quantitative histological evaluation of kidneys at 6 mo after treatment confirmed that B2 treatment reduced severity of kidney tissue pathology. Treatment-associated reduction of transforming growth factor (TGF)-β1, plasminogen activator inhibitor (PAI)-1, and fibronectin (FN) provided evidence that B2 cells attenuated canonical pathways of profibrotic extracellular matrix production.

scholarly journals Solubleα-Klotho Serum Levels in Chronic Kidney Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Silverio Rotondi ◽  
Marzia Pasquali ◽  
Lida Tartaglione ◽  
Maria Luisa Muci ◽  
Giusy Mandanici ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Disease ◽  
Clinical Significance ◽  
Serum Levels ◽  
Serum Phosphate ◽  
Renal Tubules ◽  
Ckd Stage ◽  
Tubular Transport ◽  
Negative Effect

Transmembraneα-Klotho (TM-Klotho), expressed in renal tubules, is a cofactor for FGF23-receptor. Circulating soluble-α-Klotho (s-Klotho) results from TM-Klotho shedding and acts on Phosphate (P) and Calcium (Ca) tubular transport. Decreased TM-Klotho, described in experimental chronic kidney disease (CKD), prevents actions of FGF23 and lessens circulating s-Klotho. Thus, levels of s-Klotho could represent a marker of CKD-MBD. To evaluate the clinical significance of s-Klotho in CKD we assayed serum s-Klotho and serum FGF23 in 68 patients (age58±15; eGFR45±21 mL/min). s-Klotho was lower than normal (519±183versus845±330 pg/mL,P<.0001) in renal patients and its reduction was detectable since CKD stage 2 (P<.01). s-Klotho correlated positively with eGFR and serum calcium (Cas) and negatively with serum phosphate (Ps), PTH and FGF23. FGF23 was higher than normal (73±51versus36±11,P<.0002) with significantly increased levels since CKD stage 2 (P<.001). Our data indicate a negative effect of renal disease on circulating s-Klotho starting very early in CKD. Assuming that s-Klotho mirrors TM-Klotho synthesis, low circulating s-Klotho seems to reflect the ensuing of tubular resistance to FGF23, which, accordingly, is increased. We endorse s-Klotho as an early marker of CKD-MBD.

Abstract 188: Loss of Renal Prolyl Carboxypeptidase in Mice With Chronic Kidney Disease

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Orly Leiva ◽  
Khalid M Elased ◽  
Mariana Morris ◽  
Nadja Grobe
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Protein Expression ◽  
Western Blot ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Left Renal Artery ◽  
Renal Tubules ◽  
Ang Ii ◽  
Chronic Kidney Injury

There are 26 million adults with chronic kidney disease (CKD) in the U.S. and the incidence continues to increase. It is well documented that the activation of the renin angiotensin system and the elevated formation of angiotensin (Ang) II both contribute to renal pathophysiology in CKD. Emerging evidence suggests that the Ang II degrading protease prolyl carboxypeptidase (PCP) is renoprotective. Thus, we investigated protein expression and activity of renal PCP using immunofluorescence, western blot and mass spectrometry in a mouse model of CKD. Renal injury in male C57Bl6 mice was caused by constriction of the left renal artery using silver clips (2K1C-method). Blood pressure measurements by radiotelemetry revealed a significant increase of 36.1 ± 3.9 mm Hg in 2K1C animals compared with control animals 1 week after clip placement (p<0.0001). Using immunofluorescence and confocal microscopy, PCP was localized in the Bowman’s capsule of the glomerulus and in proximal and distal renal tubules. Western blot analysis showed PCP was significantly reduced in clipped 2K1C kidneys compared to unclipped kidneys of the 2K1C mice or compared to control mice (clipped 0.04 ± 0.02 vs unclipped 0.58 ± 0.16 vs control 0.65 ± 0.18, p < 0.05). In addition, renal PCP enzyme activity was found to be markedly reduced in 2K1C kidneys as assessed by mass spectrometric based enzyme assays (clipped 37.1 ± 4.3 pmol Ang-(1-7)/h/μg vs unclipped 77.3 ± 12.3 pmol Ang-(1-7)/h/μg vs control 120.7 ± 14.7 pmol Ang-(1-7)/h/μg, p < 0.01). In contrast, protein expression of prolyl endopeptidase, another enzyme capable of converting Ang II into Ang-(1-7), was not affected. Notably, renal pathologies were exacerbated in the 2K1C model as revealed by a significant increase in mesangial expansion (clipped 34.6 ± 3.1 vs unclipped 52.1 ± 4.0 vs control 1.2 ± 2.1, p < 0.0001) and renal fibrosis (clipped 57.5 ± 0.9 vs unclipped 33.0 ± 0.7 vs control 3.3 ± 0.2, p < 0.0001). Results suggest that PCP is suppressed in chronic kidney injury and that this downregulation may attenuate renoprotective effects via impaired Ang II degradation by PCP. Therefore, Ang II processing by PCP may have clinical implications in patients with renal pathologies.

MO761THE CONTRIBUTION OF HIGH-PHOSPHORUS IN EXTRACELLULAR MATRIX ACCUMULATION OF VALVULAR CALCIFICATION IN CHRONIC KIDNEY DISEASE

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Liting Wang ◽  
Yuxia Zhang ◽  
Yujia Wang ◽  
Rining Tang
Keyword(s):  
Chronic Kidney Disease ◽  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Kidney Disease ◽  
Early Stage ◽  
Umbilical Vein ◽  
Akt Pathway ◽  
Protein Levels ◽  
Valvular Calcification ◽  
High Phosphorus

Abstract Background and Aims The characteristics of valvular calcification (VC) in early stage are extracellular matrix (ECM) accumulation and muti-cells activation. In our previous work, we found high-phosphorus (HP) diet aggravated ECM accumulation in both aortic valve and mitral valve in rats with chronic kidney disease (CKD). However, the underlying mechanism of HP contribution in ECM accumulation of CKD-induced VC is still unknown. Method canine valvular interstitial cells (VICs), valvular endothelial cells (VECs) and human umbilical vein endothelial cells (HUVECs) were used in this study. CKD mice (C57b and Tek-EGFP-PolyA) was build by 0.2% adenine-diet for 6 weeks and HP diet/NP diet for 10 weeks. Results As for VICs, HP induced qVICs transfer into aVICs, not oVICs, which was characterized with upregulated level of smoothelin and viemitin. There was no calcium accumulation was observed, suggesting that VICs do not have the ability to synthesize calcium crystals under pure HP intervention. As for VECs, aVICs activated by HP induced VECs EndMT in a transwell-assay, which was characterized with decreasing protein levels of endothelial markers (CD31, vWF, VE-cadherin) and increasing protein levels of mesenchymal makers (α-SMA, FSP1, N-cadherin). Then, IL-8 was found as the main factor releasing from VICs to induce VECs EndMT. In vitro, the concentration of IL-8 in the lower chamber could reach 2-4ng/ml. Reparixin was used to inhibit IL-8 receptor of VECs, which could relive aVICs-induced EndMT. In vivo, the expression of valve CXCL-2 (the mouse IL8 functional homolog) was increased in HP-diet compared with NP-diet, though the serum level of CXCL-2 was similar between two groups. AAV9-sm22a-CXCL-2 and Reparixin could inhibit VECs EndMT by inhibiting VICs relasing CXCL-2 and inhibiting VECs IL-8 receptor in CKD mice of Tek-EGFP-PolyA respectively. Then, IL-8 was found to induced VECs EndMT by miR-214-3p/PTEN/Akt pathway. Inhibiting EndMT by blocking IL-8/miR-214-3p could alleviate ECM accumulation. Conclusion HP could induce qVICs transfer into aVICs, and aVICs could cause VECs EndMT via IL-8/miR-214-3p/PTEN/Akt pathway. Both take part in ECM accumulation in CKD-induced VC.

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