Role of lactosylceramide and MAP kinase in the proliferation of proximal tubular cells in human polycystic kidney disease.

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either the PKD1 or PKD2 gene. While kidney failure typically occurs in adulthood, the disease starts in utero. The best change of preserving renal function long term might be the use of agents with few side effects as early as possible. For this approach, both better early prognostic stratification and novel treatment options are needed. The pediatric phase of ADPKD, while kidney function is still normal and before significant tissue destruction has occurred could be the best stage both to identify and study prognostic biomarkers as well as to identify novel targets for early treatment. Copeptin (a surrogate for vasopressin), epidermal growth factor (EGF) ( a measure for functional tubular mass) and monocyte chemoattractant protein-1 (MCP-1) ( a chemoattractant for macrophages) are associated with severity and hold prognostic value in adults but remain unstudied in the early disease stage. Kidneys from adults with ADPKD exhibit macrophage infiltration, and a prominent role of MCP-1 secretion by tubular epithelial cells is suggested from rodent models. Method A monocentric cross-sectional study in a tertiary referral center was performed. All consenting genotyped ADPKD patients attending the outpatient pediatric ADPKD clinic of the university hospital of Leuven and age, sex and BMI matched healthy controls were included between June and October 2017. Plasma copeptin, urinary EGF and urinary MCP-1 were evaluated. MCP-1 was studied in mouse collecting duct cells, human proximal tubular cells and fetal kidney tissue. Results 53 genotyped ADPKD patients and 53 controls were included. Mean (SD) age was 10.4 (5.9) vs 10.5 (6.1) years (P=0.543), and eGFR 122.7 (39.8) vs 114.5 (23.1) ml/min/1.73 m2 (P= 0.177) in patients vs controls respectively. Outcome parameters in table. Plasma copeptin and EGF secretion were comparable between both groups. Median (IQR) urinary MCP-1 (pg/mg creatinine) was significantly higher in ADPKD patients (185.4 (213.8)) compared to controls (154.7 (98.0)) (P= 0.010). Human proximal tubular cells with a heterozygous PKD1 mutation and mouse collecting duct cells with a PKD1 knockout exhibited increased MCP-1 secretion triggered by fetal bovine serum. Human fetal ADPKD kidneys displayed prominent MCP-1 immunoreactivity and M2 macrophage infiltration. Conclusion An increase in tubular MCP-1 secretion is an early event in ADPKD, long before kidney function decline and in children with few kidney cysts. MCP-1 is a promising early disease severity marker and a potential treatment target.

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Role of the N-terminal polycystic kidney disease domain in chitin degradation by chitinase A from a marine bacterium, Alteromonas sp. strain O-7

Journal of Applied Microbiology ◽

10.1111/j.1365-2672.2005.02630.x ◽

2005 ◽

Vol 99 (3) ◽

pp. 551-557 ◽

Cited By ~ 30

Author(s):

H. Orikoshi ◽

S. Nakayama ◽

C. Hanato ◽

K. Miyamoto ◽

H. Tsujibo

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Marine Bacterium ◽

Polycystic Kidney ◽

Chitin Degradation ◽

Chitinase A

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Ankhd1 enhances polycystic kidney disease development via promoting proliferation and fibrosis

10.1101/2020.03.04.977017 ◽

2020 ◽

Author(s):

Foteini Patera ◽

Guillaume M Hautbergue ◽

Patricia Wilson ◽

Paul C Evans ◽

Albert CM Ong ◽

...

Keyword(s):

Cell Proliferation ◽

Kidney Disease ◽

Polycystic Kidney Disease ◽

Therapeutic Benefit ◽

Polycystic Kidney ◽

Molecular Events ◽

Proliferative Growth ◽

Kh Domain ◽

Autosomal Dominant Polycystic Kidney

ABSTRACTAutosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common genetic kidney disorder resulting in 10% of patients with renal failure. The molecular events responsible for the relentless growth of cysts are not defined. Thus, identification of novel drivers of ADPKD may lead to new therapies. Ankyrin Repeat and Single KH domain-1 (ANKHD1) controls cancer cell proliferation, yet its role in ADPKD is unexplored. Here, we present the first data that identify ANKHD1 as a driver of proliferative growth in cellular and mouse models of ADPKD. Using the first Ankhd1-deficient mice, we demonstrate that Ankhd1 heterozygosity potently reduces cystic growth and fibrosis, in a genetically orthologous mouse model of ADPKD. We performed transcriptome-wide profiling of patient-derived ADPKD cells with and without ANKHD1 siRNA silencing, revealing a major role for ANKHD1 in the control of cell proliferation and matrix remodelling. We validated the role of ANKHD1 in enhancing proliferation in patient-derived cells. Mechanistically ANKHD1 promotes STAT5 signalling in ADPKD mice. Hence, ANKHD1 is a novel driver of ADPKD, and its inhibition may be of therapeutic benefit.

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Molecular Pathways and Therapies in Autosomal-Dominant Polycystic Kidney Disease

Physiology ◽

10.1152/physiol.00032.2014 ◽

2015 ◽

Vol 30 (3) ◽

pp. 195-207 ◽

Cited By ~ 22

Author(s):

Takamitsu Saigusa ◽

P. Darwin Bell

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Primary Cilia ◽

Autosomal Dominant ◽

Molecular Pathways ◽

Polycystic Kidney ◽

Autosomal Dominant Polycystic Kidney ◽

Multiple Cysts ◽

Review Current

Autosomal-dominant polycystic kidney disease (ADPKD) is the most prevalent inherited renal disease, characterized by multiple cysts that can eventually lead to kidney failure. Studies investigating the role of primary cilia and polycystins have significantly advanced our understanding of the pathogenesis of PKD. This review will present clinical and basic aspects of ADPKD, review current concepts of PKD pathogenesis, evaluate potential therapeutic targets, and highlight challenges for future clinical studies.

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