Klotho and activin A in kidney injury: plasma Klotho is maintained in unilateral obstruction despite no upregulation of Klotho biosynthesis in the contralateral kidney

Nordholm, Anders; Mace, Maria L; Gravesen, Eva; Hofman-Bang, Jacob; Morevati, Marya; Ølgaard, Klaus; Lewin, Ewa

doi:10.1152/ajprenal.00528.2017

Cited by 30 publications

(40 citation statements)

References 71 publications

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“…Although Wnt signalling have been implied in the regeneration of injured of kidney tissue, persistent activation and dysregulation of the Wnt pathways underlie fibrosis and progressive renal failure [ 28 ]. In agreement with previously reported results from our group, UUO was associated with induction of expression of genes related to fibrosis [ 27 ]. ICG-001 abolished the induced expression of pro-fibrotic genes in the UUO experiment, confirming the bioavailability and effect of the compound, in agreement with previous results by Hao et al [ 19 ].…”

Section: Discussionsupporting

confidence: 93%

“…Renal fibrosis is the final common pathway of all progressive renal diseases [ 23 ]. Several studies and previous results from our group have shown that kidney injury could reactivate developmental programs involved in nephrogenesis, attempting renal repair [ 24 – 27 ]. Wnt family members and factors controlling Wnt function are critical morphogens in the developing kidney [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

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Effect of inhibition of CBP-coactivated β-catenin-mediated Wnt signalling in uremic rats with vascular calcifications

et al. 2018

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Uremic vascular calcification is a regulated cell-mediated process wherein cells in the arterial wall transdifferentiate to actively calcifying cells resulting in a process resembling bone formation. Wnt signalling is established as a major driver for vessel formation and maturation and for embryonic bone formation, and disturbed Wnt signalling might play a role in vascular calcification. ICG-001 is a small molecule Wnt inhibitor that specifically targets the coactivator CREB binding protein (CBP)/β-catenin-mediated signalling. In the present investigation we examined the effect of ICG-001 on vascular calcification in uremic rats. Uremic vascular calcification was induced in adult male rats by 5/6-nephrectomy, high phosphate diet and alfacalcidol. The presence of uremic vascular calcification in the aorta was associated with induction of gene expression of the Wnt target gene and marker of proliferation, cyclinD1; the mediator of canonical Wnt signalling, β-catenin and the matricellular proteins, fibronectin and periostin. Furthermore, genes from fibrosis-related pathways, TGF-β and activin A, as well as factors related to epithelial-mesenchymal transition, snail1 and vimentin were induced. ICG-001 treatment had significant effects on gene expression in kidney and aorta from healthy rats. These effects were however limited in uremic rats, and treatment with ICG-001 did not reduce the Ca-content of the uremic vasculature.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Effect of inhibition of CBP-coactivated β-catenin-mediated Wnt signalling in uremic rats with vascular calcifications

et al. 2018

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“…A mouse model of CKD revealed upregulation of activin expression in the skeleton, vasculature, heart, and kidneys 23 . In addition, a ligand trap for the activin type IIA receptor exhibited beneficial effects in murine CKD models, alleviating vascular disease and renal fibrosis 35 , renal osteodystrophy 36 and nephrogenic anemia 37 . These previous findings implied a causative role of activin A in the pathogenesis of CKD and its potential role as a target of treatment.…”

Section: Discussionmentioning

confidence: 99%

Serum Activin A Levels and Renal Outcomes After Coronary Angiography

Tsai

Chou

et al. 2020

Sci Rep

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prevention for contrast-induced nephropathy (cin) is limited by the lack of a single predictor. As activin A is upregulated in heart failure and chronic kidney disease, we aimed to clarify the association between activin A levels and renal outcomes after coronary angiography (CAG). This prospective observational study included 267 patients who received CAG between 2009 and 2015. CIN was defined as elevation of serum creatinine to >0.5 mg/dL or to >25% above baseline within 48 hours after CAG. During follow-up, laboratory parameters were measured every 3-6 months. Renal decline was defined as>2-fold increase in serum creatinine or initiation of dialysis. The patients were stratified into tertiles according to serum activin A levels at baseline. High activin A tertile was significantly associated more CIN and renal function decline compared to low activin A tertile (all p < 0.001). After adjusting potential confounding factors, high serum activin A tertiles was associated to CIN (Odds ratio 4.49, 95% CI 1.07-18.86, p = 0.040) and renal function decline (Hazard ratio 4.49, 95% CI 1.27-11.41, p = 0.017) after CAG. Contrast-induced nephropathy (CIN) refers to acute kidney injury (AKI) caused by the contrast medium administered for angiographic procedures, which is one of the major causes of in-hospital AKI 1. Although CIN is generally transient and reversible, it remains an important clinical issue due to its high incidence and association with adverse outcomes. Previous studies showed that CIN affects 7-25% of patients receiving angiographic procedures 2,3. Moreover, CIN increases hospitalization duration, medical costs, long-term morbidity, and mortality 4-7. The clinical significance of CIN is further supported by the fact that even mild elevation of serum creatinine levels after administration of contrast medium is associated with progressive renal decline and development of end-stage renal disease (ESRD) 8. While it has been accepted that the prevention of CIN is essentially important, the available strategies for treating established CIN remain conservative and limited to fluid and electrolyte management 9. Currently, CIN preventive measures start with risk stratification, which involves non-modifiable fixed risk factors, including preexisting chronic kidney disease (CKD), diabetes mellitus, congestive heart failure (CHF), advanced age, female sex, and modifiable risk factors, including hypotension, anemia, concurrent use of nephrotoxic drugs, hypercholesterolemia, dehydration, hyperglycemia, and the type and volume of contrast medium used 10. For patients at low risk, oral or intravenous hydration are appropriate preventive measures. On the other hand, for patients at intermediate or high risk, correction of the modifiable risk factors should be considered, which include intravenous crystalloid fluid, N-acetylcysteine, ascorbic acid, and statins 10,11. While the preventive strategy of CIN depends on risk stratification, a single and reliable predictor of CIN remains absent to date. Activin A is a secreted cytok...

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“…In experimental studies, elevated activin A was derived directly from renal tubule epithelial cells in streptozotocin-treated38 and UUO25 rat models, from myofibroblasts in Alport CKD mice,22 25 renal interstitial cells in Ldlr –/– high fat-fed mice with ablative CKD,22 infiltrating macrophages in lupus nephritis mice23 and glomerular culture supernatants in an anti-Thy1 glomerulonephritis rat model 39. Furthermore, while UUO induced activin A gene expression in the kidney and its release into the circulation, these findings were not observed in the plasma, contralateral kidney or remnant kidney of unilaterally nephrectomized rats having similar fall in total GFR, suggesting the obstructed kidney as the source 24. In our human diabetes studies, albuminuria, reflective of kidney injury, directly correlated with activin A in plasma and urine.…”

Section: Discussionmentioning

confidence: 96%

“…However, activin A becomes abundantly expressed in the injured kidney in experimental models of acute kidney injury (AKI),19 20 glomerulonephritis and CKD 21–23. Circulating activin A levels doubled in unilateral ureter obstruction (UUO) rats while levels remained unchanged in unilateral nephrectomized controls with similar kidney function, suggesting the obstructed kidney as the source 24. Renal tubular cells release activin A, which acts as a paracrine factor that promotes fibroblast proliferation, contributing to kidney fibrosis and CKD progression 17 19 25.…”

Section: Introductionmentioning

confidence: 99%

Senescence marker activin A is increased in human diabetic kidney disease: association with kidney function and potential implications for therapy

Bian

Griffin

Zhu

et al. 2019

BMJ Open Diab Res Care

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ObjectiveActivin A, an inflammatory mediator implicated in cellular senescence-induced adipose tissue dysfunction and profibrotic kidney injury, may become a new target for the treatment of diabetic kidney disease (DKD) and chronic kidney diseases. We tested the hypothesis that human DKD-related injury leads to upregulation of activin A in blood and urine and in a human kidney cell model. We further hypothesized that circulating activin A parallels kidney injury markers in DKD.Research design and methodsIn two adult diabetes cohorts and controls (Minnesota, USA; Galway, Ireland), the relationships between plasma (or urine) activin A, estimated glomerular filtration rate (eGFR) and DKD injury biomarkers were tested with logistic regression and correlation coefficients. Activin A, inflammatory, epithelial-mesenchymal-transition (EMT) and senescence markers were assayed in human kidney (HK-2) cells incubated in high glucose plus transforming growth factor-β1 or albumin.ResultsPlasma activin A levels were elevated in diabetes (n=206) compared with controls (n=76; 418.1 vs 259.3 pg/mL; p<0.001) and correlated inversely with eGFR (rs=−0.61; p<0.001; diabetes). After eGFR adjustment, only albuminuria (OR 1.56, 95% CI 1.16 to 2.09) and tumor necrosis factor receptor-1 (OR 6.40, 95% CI 1.08 to 38.00) associated with the highest activin tertile. Albuminuria also related to urinary activin (rs=0.65; p<0.001). Following in vitro HK-2 injury, activin, inflammatory, EMT genes and supernatant activin levels were increased.ConclusionsCirculating activin A is increased in human DKD and correlates with reduced kidney function and kidney injury markers. DKD-injured human renal tubule cells develop a profibrotic and inflammatory phenotype with activin A upregulation. These findings underscore the role of inflammation and provide a basis for further exploration of activin A as a diagnostic marker and therapeutic target in DKD.

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Klotho and activin A in kidney injury: plasma Klotho is maintained in unilateral obstruction despite no upregulation of Klotho biosynthesis in the contralateral kidney

Cited by 30 publications

References 71 publications

Effect of inhibition of CBP-coactivated β-catenin-mediated Wnt signalling in uremic rats with vascular calcifications

Effect of inhibition of CBP-coactivated β-catenin-mediated Wnt signalling in uremic rats with vascular calcifications

Serum Activin A Levels and Renal Outcomes After Coronary Angiography

Senescence marker activin A is increased in human diabetic kidney disease: association with kidney function and potential implications for therapy

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