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Pharmacological reversal of renal cysts from secretion to absorption suggests a potential therapeutic strategy for managing autosomal dominant polycystic kidney disease.

ABSTRACT: Autosomal-dominant polycystic kidney disease (ADPKD) induces a secretory phenotype, resulting in multiple fluid-filled cysts. We have previously demonstrated that VX-809, a corrector of the cystic fibrosis transmembrane conductance regulator (CFTR), reduces cyst growth. Here, we show that in normal mice CFTR is located within the cells and also at the apical and basolateral membranes. However, in polycystic kidney disease (pkd1)-knockout mice, CFTR was located at the plasma membrane, consistent with its role in cAMP-dependent fluid secretion. In cystic mice, VX-809 treatment increased CFTR levels at the apical membrane and reduced its association with the endoplasmic reticulum. Surprisingly, VX-809 treatment significantly increased CFTR's co-localization with the basolateral membrane in cystic mice. Na+/H+ exchanger 3 (NHE3) is present in pkd1-knockout and normal mice and in proximal tubule-derived, cultured pkd1-knockout cells. VX-809 increased the expression, activity, and apical plasma membrane localization of NHE3. Co-localization of epithelial sodium channel (ENaC) with the plasma membrane was reduced in cysts in pkd1-knockout mice, consistent with an inability of the cysts to absorb fluid. Interestingly, in the cystic mice, VX-809 treatment increased ENaC levels at the apical plasma membrane consistent with fluid absorption. Thus, VX-809 treatment of pkd1-null mouse kidneys significantly affected CFTR, NHE3, and ENaC, altering the cyst phenotype from one poised toward fluid secretion toward one more favorable for absorption. VX-809 also altered the location of CFTR but not of NHE3 or ENaC in normal mice. Given that VX-809 administration is safe, it may have potential utility for treating patients with ADPKD.

SUBMITTER: Yanda MK

PROVIDER: S-EPMC6851297 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Pharmacological reversal of renal cysts from secretion to absorption suggests a potential therapeutic strategy for managing autosomal dominant polycystic kidney disease.

Yanda Murali K MK Cha Boyoung B Cebotaru Cristina V CV Cebotaru Liudmila L

The Journal of biological chemistry 20190930 45

Autosomal-dominant polycystic kidney disease (ADPKD) induces a secretory phenotype, resulting in multiple fluid-filled cysts. We have previously demonstrated that VX-809, a corrector of the cystic fibrosis transmembrane conductance regulator (CFTR), reduces cyst growth. Here, we show that in normal mice CFTR is located within the cells and also at the apical and basolateral membranes. However, in polycystic kidney disease (<i>pkd1</i>)-knockout mice, CFTR was located at the plasma membrane, cons ...[more]

PMID: 31570523

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Project description:BACKGROUND AND OBJECTIVES:In autosomal dominant polycystic kidney disease (ADPKD), the GFR often remains normal despite significant nephron loss. Proximal tubular secretory clearance may be reduced in ADPKD before detectable changes in GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:We used targeted mass spectrometry to quantify secretory solutes from blood and urine samples from 31 patients with ADPKD and preserved GFR (mean eGFR =111±11 ml/min per 1.73 m2) and 25 healthy control individuals as well as from 95 patients with ADPKD and reduced GFR (mean eGFR =53±21 ml/min per 1.73 m2) and 92 individuals with non-ADPKD CKD. We used linear regression to compare the fractional excretion of each solute between ADPKD and control groups. Among 112 patients with ADPKD, we used linear regression to determine associations of solute fractional excretion with height-adjusted total kidney volume. RESULTS:After adjusting for demographics, clinical characteristics, and kidney function measures, the fractional excretions of three secretory solutes were lower in patients with ADPKD and preserved GFR compared with healthy individuals: 52% lower cinnamoylglycine excretion (95% confidence interval, 24% to 70%), 53% lower tiglylglycine excretion (95% confidence interval, 23% to 71%), and 91% lower xanthosine excretion (95% confidence interval, 83% to 95%). In addition to lower excretions of tiglylglycine and xanthosine, patients with ADPKD and reduced GFR also demonstrated 37% lower dimethyluric acid excretion (95% confidence interval, 21% to 50%), 58% lower hippurate excretion (95% confidence interval, 48% to 66%), 48% lower isovalerylglycine excretion (95% confidence interval, 37% to 56%), and 31% lower pyridoxic acid excretion (95% confidence interval, 16% to 42%) compared with patients with non-ADPKD CKD and comparable eGFR. Among patients with ADPKD, solute fractional excretions were not associated with differences in kidney volume. CONCLUSIONS:Patients with ADPKD and preserved and reduced GFR demonstrate lower tubular secretory solute excretion compared with healthy controls and patients with non-ADPKD CKD. Our results suggest that tubular secretion is impaired in ADPKD independent of GFR.

Project description:Purpose To define the magnetic resonance (MR) imaging prevalence of pancreatic cysts in a cohort of patients with autosomal dominant polycystic kidney disease (ADPKD) compared with a control group without ADPKD that was matched for age, sex, and renal function. Materials and Methods In this HIPAA-compliant, institutional review board-approved study, all patients with ADPKD provided informed consent; for control subjects, informed consent was waived. Patients with ADPKD (n = 110) with mutations identified in PKD1 or PKD2 and control subjects without ADPKD or known pancreatic disease (n = 110) who were matched for age, sex, estimated glomerular filtration rate, and date of MR imaging examination were evaluated for pancreatic cysts by using axial and coronal single-shot fast spin-echo T2-weighted images obtained at 1.5 T. Total kidney volume and liver volume were measured. Univariate and multivariable logistic regression analyses were conducted to evaluate potential associations between collected variables and presence of pancreatic cysts among patients with ADPKD. The number, size, location, and imaging characteristics of the cysts were recorded. Results Patients with ADPKD were significantly more likely than control subjects to have at least one pancreatic cyst (40 of 110 patients [36%] vs 25 of 110 control subjects [23%]; P = .027). In a univariate analysis, pancreatic cysts were more prevalent in patients with ADPKD with mutations in PKD2 than in PKD1 (21 of 34 patients [62%] vs 19 of 76 patients [25%]; P = .0002). In a multivariable logistic regression model, PKD2 mutation locus was significantly associated with the presence of pancreatic cysts (P = .0004) and with liver volume (P = .038). Patients with ADPKD and a pancreatic cyst were 5.9 times more likely to have a PKD2 mutation than a PKD1 mutation after adjusting for age, race, sex, estimated glomerular filtration rate, liver volume, and total kidney volume. Conclusion Pancreatic cysts were more prevalent in patients with ADPKD with PKD2 mutation than in control subjects or patients with PKD1 mutation. (©) RSNA, 2016 Online supplemental material is available for this article.

Dataset Information

Pharmacological reversal of renal cysts from secretion to absorption suggests a potential therapeutic strategy for managing autosomal dominant polycystic kidney disease.

Publications

Pharmacological reversal of renal cysts from secretion to absorption suggests a potential therapeutic strategy for managing autosomal dominant polycystic kidney disease.

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