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Gremlin promotes peritoneal membrane injury in an experimental mouse model and is associated with increased solute transport in peritoneal dialysis patients.

ABSTRACT: The peritoneal membrane becomes damaged in patients on peritoneal dialysis (PD). Gremlin 1 (GREM1) inhibits bone morphogenic proteins (BMPs) and plays a role in kidney development and fibrosis. We evaluated the role of gremlin in peritoneal fibrosis and angiogenesis. In a cohort of 32 stable PD patients, GREM1 concentration in the peritoneal effluent correlated with measures of peritoneal membrane damage. AdGrem1, an adenovirus to overexpress gremlin in the mouse peritoneum, induced submesothelial thickening, fibrosis, and angiogenesis in C57BL/6 mice, which was associated with decreased expression of BMP4 and BMP7. There was evidence of mesothelial cell transition to a mesenchymal phenotype with increased ? smooth muscle actin expression and suppression of E-cadherin. Some of the GREM1 effects may be reversed with recombinant BMP7 or a pan-specific transforming growth factor ? (TGF-?) antibody. Neovascularization was not inhibited with a TGF-? antibody, suggesting a TGF-?-independent angiogenic mechanism. Swiss/Jackson Laboratory (SJL) mice, which are resistant to TGF-?-induced peritoneal fibrosis, responded in a similar fashion to AdGrem1 as did C57BL/6 mice with fibrosis, angiogenesis, and mesothelial-to-mesenchymal transition. GREM1 was associated with up-regulated TGF-? expression in both SJL and C57BL/6 mice, but SJL mice demonstrated a defective TGF-?-induced GREM1 expression. In summary, GREM1 induces fibrosis and angiogenesis in mouse peritoneum and is associated with increased solute transport in these PD patients.

SUBMITTER: Siddique I

PROVIDER: S-EPMC5707198 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Gremlin promotes peritoneal membrane injury in an experimental mouse model and is associated with increased solute transport in peritoneal dialysis patients.

Siddique Imad I Curran Simon P SP Ghayur Ayesha A Liu Limin L Shi Wei W Hoff Catherine M CM Gangji Azim S AS Brimble K Scott KS Margetts Peter J PJ

The American journal of pathology 20140903 11

The peritoneal membrane becomes damaged in patients on peritoneal dialysis (PD). Gremlin 1 (GREM1) inhibits bone morphogenic proteins (BMPs) and plays a role in kidney development and fibrosis. We evaluated the role of gremlin in peritoneal fibrosis and angiogenesis. In a cohort of 32 stable PD patients, GREM1 concentration in the peritoneal effluent correlated with measures of peritoneal membrane damage. AdGrem1, an adenovirus to overexpress gremlin in the mouse peritoneum, induced submesotheli ...[more]

PMID: 25194662

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Project description:Background and objectivesResidual kidney function is important to the health and wellbeing of patients with ESKD. We tested whether the kidney clearances of proximal tubular secretory solutes are associated with burden of uremic and heart failure symptoms among patients on peritoneal dialysis with residual kidney function.Design, setting, participants, & measurementsWe enrolled 29 patients on incident peritoneal dialysis with residual urine output >250 ml daily. We used targeted liquid chromatography-mass spectrometry to quantify plasma, 24-hour urine, and peritoneal dialysate concentrations of ten tubular secretory solutes. We calculated the kidney and peritoneal dialysis clearances of each secretory solute, creatinine, and urea, and we estimated a composite kidney and peritoneal secretion score. We assessed for uremic symptoms using the Dialysis Symptom Index and heart failure-related symptoms using the Kansas City Cardiomyopathy Questionnaire. We used linear regression to determine associations of composite secretory solute clearances and GFRurea+Cr with Dialysis Symptom Index symptom score and Kansas City Cardiomyopathy Questionnaire summary score.ResultsMean residual kidney clearances of creatinine and urea were 8±5 and 9±6 ml/min per 1.73 m2, respectively, and mean GFRurea+Cr was 8±5 ml/min per 1.73 m2. The residual kidney clearances of most secretory solutes were considerably higher than creatinine and urea clearance, and also, they were higher than their respective peritoneal dialysis clearances. After adjustments for age and sex, each SD higher composite kidney secretion score was associated with an 11-point lower Dialysis Symptom Index score (95% confidence interval, -20 to -1; P=0.03) and a 12-point higher Kansas City Cardiomyopathy Questionnaire score (95% confidence interval, 0.5- to 23-point higher score; P=0.04). Composite peritoneal dialysis secretion score was not associated with either symptom assessment.ConclusionsResidual kidney clearances of secretory solutes are higher than peritoneal dialysis clearances. Kidney clearances of secretory solutes are associated with patient-reported uremic and heart failure-related symptoms.

Dataset Information

Gremlin promotes peritoneal membrane injury in an experimental mouse model and is associated with increased solute transport in peritoneal dialysis patients.

Publications

Gremlin promotes peritoneal membrane injury in an experimental mouse model and is associated with increased solute transport in peritoneal dialysis patients.

Similar Datasets

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