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1.
Nat Commun ; 15(1): 371, 2024 Jan 08.
Article in English | MEDLINE | ID: mdl-38191531

ABSTRACT

Aurora Kinase A (AURKA) promotes cell proliferation and is overexpressed in different types of polycystic kidney disease (PKD). To understand AURKA's role in regulating renal cyst development we conditionally deleted the gene in mouse models of Autosomal Dominant PKD (ADPKD) and Joubert Syndrome, caused by Polycystin 1 (Pkd1) and Inositol polyphosphate-5-phosphatase E (Inpp5e) mutations respectively. We show that while Aurka is dispensable for collecting duct development and homeostasis, its deletion prevents cyst formation in both disease models. Cross-comparison of transcriptional changes implicated AKT signaling in cyst prevention and we show that (i) AURKA and AKT physically interact, (ii) AURKA regulates AKT activity in a kinase-independent manner and (iii) inhibition of AKT can reduce disease severity. AKT activation also regulates Aurka expression, creating a feed-forward loop driving renal cystogenesis. We find that the AURKA kinase inhibitor Alisertib stabilises the AURKA protein, agonizing its cystogenic functions. These studies identify AURKA as a master regulator of renal cyst development in different types of PKD, functioning in-part via AKT.


Subject(s)
Aurora Kinase A , Cysts , Polycystic Kidney Diseases , Polycystic Kidney, Autosomal Dominant , Animals , Mice , Aurora Kinase A/genetics , Phosphoric Monoester Hydrolases , Polycystic Kidney Diseases/genetics , Polycystic Kidney Diseases/prevention & control , Proto-Oncogene Proteins c-akt/genetics
2.
FASEB J ; 33(2): 2848-2857, 2019 02.
Article in English | MEDLINE | ID: mdl-30321068

ABSTRACT

Cilia are hair-like structures that function like antennae to detect chemical and mechanical signals in the environment. Recently, phosphoinositides were shown to play an important role in cilia assembly and disassembly. However, the precise molecular and cellular mechanisms underlying this process remain unknown. Here, we report that suppression of apical phosphatidylinositol 4,5- bisphosphate [PtdIns(4,5)P2], by overexpressing apically targeted PtdIns(4,5)P2 phosphatase or by knocking down type I phosphatidylinositol 4-phosphate 5-kinase (Pip5k1), leads to ciliogenesis defects and polycystic kidney disease (PKD) in zebrafish embryos that phenocopied inpp5e mutant, a Joubert syndrome model. We further demonstrate that decreased expression of apical PtdIns(4,5)P2 disrupted apical ezrin recruitment, F-actin organization, and basal body docking. Moreover, the ciliogenesis and polycystic kidney defects in PtdIns(4,5)P2-depleted embryos can be rescued by overexpression of ezrin. Finally, Pip5k1a overexpression rescued the ciliogenesis defects and PKD phenotypes in Inpp5e-depleted embryos. Taken together, our results reveal that apical PtdIns(4,5)P2 is essential for ciliogenesis and the prevention of PKD and suggest a novel possibility for treating PKD and other human ciliopathies.-Xu, W., Jin, M., Huang, W., Wang, H., Hu, R., Li, J., Cao, Y. Apical PtdIns(4,5)P2 is required for ciliogenesis and suppression of polycystic kidney disease.


Subject(s)
Cell Membrane/metabolism , Cilia/physiology , Phosphatidylinositol 4,5-Diphosphate/metabolism , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Polycystic Kidney Diseases/prevention & control , Zebrafish/physiology , Actins/metabolism , Animals , Humans , Phosphotransferases (Alcohol Group Acceptor)/genetics , Polycystic Kidney Diseases/metabolism , Polycystic Kidney Diseases/pathology , Zebrafish/embryology
3.
Nefrología (Madrid) ; 38(2): 190-196, mar.-abr. 2018. mapas, tab, graf
Article in Spanish | IBECS | ID: ibc-171087

ABSTRACT

Introducción: La poliquistosis renal autosómica dominante es la enfermedad renal hereditaria más frecuente aunque los datos disponibles generalmente son tras el inicio del tratamiento renal sustitutivo. Objetivo: Conocer la situación global de la poliquistosis renal autosómica dominante en el ámbito sanitario de Granada. Material y métodos: Desde enero 2007 hasta diciembre 2016 hemos recogido información clínica, familiar y demográfica de todos los pacientes con poliquistosis renal autosómica dominante, estuvieran o no en tratamiento renal sustitutivo, atendidos en el área de Granada. Se han utilizado los programas informáticos SPSS 15.0 y GenoPro. Resultados: Mil ciento siete pacientes diagnosticados, el 50,6% son varones. Se han estudiado 4-6 generaciones/familia. El 99,1% de raza caucásica. Hay áreas geográficas con mayor concentración. No hay antecedentes familiares en el 2,43%. La edad media de diagnóstico es de 34±17,8 años y en el 57,7% de los casos, el diagnóstico se produce después de tener descendencia. El principal motivo de diagnóstico son los antecedentes familiares (46,4%). La edad media de entrada en técnica es de 54,2±11,05 años. El 96,3% de los fallecidos tenían algún grado de insuficiencia renal en el momento del exitus. La edad media del exitus es de 60,9±14,10 años, siendo desconocida la principal causa de muerte (33,5%) seguida de la cardiovascular (27,8%). Conclusiones: Casos y familias se concentran en algunas áreas geográficas, un número importante de individuos están sin diagnosticar, fallecen antes por causa cardiovascular y se diagnostican tarde respecto al momento reproductivo. Dado que no hay tratamiento curativo, la estrategia de prevención primaria mediante el diagnóstico genético preimplantacional adquiere protagonismo (AU)


Introduction: Although autosomal dominant polycystic kidney disease is the most common hereditary kidney disease, available data tend to be limited to after initiation of renal replacement therapy. Objective: To ascertain an overview of autosomal dominant polycystic kidney disease within the health area of Granada in southern Spain. Material and methods: From January 2007 to December 2016, we collected clinical, family and demographic information about all patients with autosomal dominant polycystic kidney disease, irrespective of whether or not they were treated with RRT, in the Granada health area. The computer software SPSS 15.0 and GenoPro were used. Results: 50.6% of the 1,107 diagnosed patients were men. 99.1% were Caucasian and 4-6 generations/family were studied. The geographical distribution was heterogeneous. There was no family history in 2.43%. The mean age of diagnosis was 34.0±17.80 years and the diagnosis was made after having offspring in 57.7% of cases. The main reason for diagnosis was family history (46.4%). The mean age of initiation of renal replacement therapy was 54.2±11.05 years. 96.3% of the deceased had some degree of renal failure at the time of death. The mean age of death was 60.9±14.10 years, the main cause of death being unknown in 33.5% of cases, followed by cardiovascular (27.8%). Conclusions: Cases and families were concentrated in certain geographical areas and a significant number of individuals were undiagnosed prior to cardiovascular death or diagnosed late after reproduction. Given that there is currently no curative treatment, the primary prevention strategy of preimplantation genetic diagnosis should play a leading role (AU)


Subject(s)
Humans , Male , Female , Young Adult , Adult , Middle Aged , Polycystic Kidney Diseases/epidemiology , Urinary Tract Infections/complications , Primary Prevention/trends , Spain/epidemiology , Sex Distribution , Polycystic Kidney Diseases/classification , Polycystic Kidney Diseases/prevention & control , Polycystic Kidney Diseases/therapy , Mortality/trends
4.
Am J Physiol Renal Physiol ; 315(1): F57-F73, 2018 07 01.
Article in English | MEDLINE | ID: mdl-29537311

ABSTRACT

Following the discovery of (R)-roscovitine's beneficial effects in three polycystic kidney disease (PKD) mouse models, cyclin-dependent kinases (CDKs) inhibitors have been investigated as potential treatments. We have used various affinity chromatography approaches to identify the molecular targets of roscovitine and its more potent analog (S)-CR8 in human and murine polycystic kidneys. These methods revealed casein kinases 1 (CK1) as additional targets of the two drugs. CK1ε expression at the mRNA and protein levels is enhanced in polycystic kidneys of 11 different PKD mouse models as well as in human polycystic kidneys. A shift in the pattern of CK1α isoforms is observed in all PKD mouse models. Furthermore, the catalytic activities of both CK1ε and CK1α are increased in mouse polycystic kidneys. Inhibition of CK1ε and CK1α may thus contribute to the long-lasting attenuating effects of roscovitine and (S)-CR8 on cyst development. CDKs and CK1s may constitute a dual therapeutic target to develop kinase inhibitory PKD drug candidates.


Subject(s)
Casein Kinase 1 epsilon/antagonists & inhibitors , Casein Kinase Ialpha/antagonists & inhibitors , Kidney/drug effects , Polycystic Kidney Diseases/prevention & control , Protein Kinase Inhibitors/pharmacology , Purines/pharmacology , Pyridines/pharmacology , Roscovitine/pharmacology , Animals , Casein Kinase 1 epsilon/genetics , Casein Kinase 1 epsilon/metabolism , Casein Kinase Ialpha/genetics , Casein Kinase Ialpha/metabolism , Catalysis , Chromatography, Affinity/methods , Disease Models, Animal , Humans , Kidney/enzymology , Kidney/pathology , Mice, Transgenic , Polycystic Kidney Diseases/enzymology , Polycystic Kidney Diseases/genetics , Polycystic Kidney Diseases/pathology , Protein Binding , Protein Kinase Inhibitors/metabolism , Purines/metabolism , Pyridines/metabolism , Roscovitine/metabolism , Signal Transduction/drug effects
5.
Am J Physiol Renal Physiol ; 315(3): F479-F486, 2018 09 01.
Article in English | MEDLINE | ID: mdl-29513074

ABSTRACT

The aim of our current study was to investigate the long-term effect and the mechanism of triptolide in an adult nonorthologous rat model of polycystic kidney disease (PKD). Male wild-type (+/+) and Cy/+ cystic Han:SPRD rats were treated with vehicle or triptolide from 4 to 16 wk of age. Rats were killed at 16 wk of age for blood, urine, and organ collection. Human-derived WT9-12 PKD cells were treated with triptolide with or without IL-6 pretreatment. Cell proliferation, apoptosis, and cytotoxicity were determined. Western blotting and immunohistochemistry analysis were performed to evaluate the activation of IL-6-JAK2-STAT3 pathway. Renal function was protected by 12 wk of triptolide treatment in cystic Han:SPRD rats as shown by reduced blood urea nitrogen, serum creatinine, and proteinuria levels. Cyst and kidney growth were also retarded by triptolide treatment in Cy/+ rats. We further found that the proliferation index was reduced by triptolide in cystic rats, which was correlated with the reduced expression of IL-6/IL-6 receptor, decreased phosphorylation of JAK2-STAT3, and increased expression of suppressor of cytokine signaling 3 (SOCS3). The inhibitory effect of triptolide was further studied in WT9-12 cells. Triptolide inhibited cell proliferation and the activation of JAK2-STAT3 pathway in PKD cells, but it increased the expression of SOCS3. Pretreatment with IL-6 attenuated the inhibitory effect of triptolide on STAT3 phosphorylation. Our study revealed a long-term beneficial effect of triptolide in PKD that was probably through inhibition of the JAK2-STAT3 pathway.


Subject(s)
Diterpenes/pharmacology , Janus Kinase 2/metabolism , Kidney/drug effects , Phenanthrenes/pharmacology , Polycystic Kidney Diseases/prevention & control , STAT3 Transcription Factor/metabolism , Animals , Apoptosis/drug effects , Blood Urea Nitrogen , Cell Line , Cell Proliferation/drug effects , Creatinine/blood , Disease Models, Animal , Disease Progression , Epoxy Compounds/pharmacology , Humans , Interleukin-6/metabolism , Kidney/enzymology , Kidney/pathology , Kidney/physiopathology , Male , Phosphorylation , Polycystic Kidney Diseases/enzymology , Polycystic Kidney Diseases/genetics , Polycystic Kidney Diseases/pathology , Proteinuria/enzymology , Proteinuria/genetics , Proteinuria/prevention & control , Rats, Transgenic , Receptors, Interleukin-6/metabolism , Signal Transduction/drug effects , Suppressor of Cytokine Signaling 3 Protein/metabolism
6.
Nephrol Dial Transplant ; 31(11): 1826-1834, 2016 11.
Article in English | MEDLINE | ID: mdl-27190325

ABSTRACT

BACKGROUND: Inflammation plays an important role in polycystic kidney disease (PKD). The current study aimed to examine the efficacy of the anti-inflammatory compound resveratrol in PKD and to investigate its underlying mechanism of action. METHODS: Male Han:SPRD (Cy/+) rats with PKD were treated with 200 mg/kg/day resveratrol or vehicle by gavage for 5 weeks. Human autosomal dominant (AD) PKD cells, three-dimensional (3D) Madin-Darby canine kidney cells and zebrafish were treated with various concentrations of resveratrol or the nuclear factor κB (NF-κB) inhibitor QNZ. RESULTS: Resveratrol treatment reduced blood urea nitrogen levels and creatinine levels by 20 and 24%, respectively, and decreased two-kidney/total body weight ratio by 15% and cyst volume density by 24% in Cy/+ rats. The proliferation index and the macrophage infiltration index were reduced by 40 and 43%, respectively, in resveratrol-treated cystic kidneys. Resveratrol reduced the levels of the pro-inflammatory factors monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α) and complement factor B (CFB) in Cy/+ rat kidneys in parallel with the decreased activity of NF-κB (p50/p65). The activation of NF-κB and its correlation with pro-inflammatory factor expression were confirmed in human ADPKD cells and kidney tissues. Resveratrol and QNZ inhibited the expression of MCP-1, TNF-α and CFB and reduced NF-κB activity in ADPKD cells. Moreover, NF-κB blockage minimized the inhibition of inflammatory factor production by resveratrol treatment. Furthermore, resveratrol or QNZ inhibited cyst formation in the 3D cyst and zebrafish models. CONCLUSIONS: The NF-κB signaling pathway is activated and partly responsible for inflammation in polycystic kidney tissues. Targeting inflammation through resveratrol could be a new strategy for PKD treatment in the future.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Inflammation/prevention & control , NF-kappa B/antagonists & inhibitors , Polycystic Kidney Diseases/prevention & control , Polycystic Kidney, Autosomal Dominant/prevention & control , Stilbenes/pharmacology , Animals , Case-Control Studies , Chemokine CCL2/metabolism , Disease Progression , Dogs , Humans , Inflammation/metabolism , Inflammation/pathology , Madin Darby Canine Kidney Cells , Male , NF-kappa B/metabolism , Polycystic Kidney Diseases/metabolism , Polycystic Kidney Diseases/pathology , Polycystic Kidney, Autosomal Dominant/metabolism , Polycystic Kidney, Autosomal Dominant/pathology , Rats , Rats, Sprague-Dawley , Resveratrol , Signal Transduction , Tumor Necrosis Factor-alpha/metabolism , Zebrafish
7.
J Am Soc Nephrol ; 27(12): 3589-3599, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27020852

ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD), characterized by the formation of numerous kidney cysts, is caused by PKD1 or PKD2 mutations and affects 0.1% of the population. Although recent clinical studies indicate that reduction of cAMP levels slows progression of PKD, this finding has not led to an established safe and effective therapy for patients, indicating the need to find new therapeutic targets. The role of TGF-ß in PKD is not clearly understood, but nuclear accumulation of phosphorylated SMAD2/3 in cyst-lining cells suggests the involvement of TGF-ß signaling in this disease. In this study, we ablated the TGF-ß type 1 receptor (also termed activin receptor-like kinase 5) in renal epithelial cells of PKD mice, which had little to no effect on the expression of SMAD2/3 target genes or the progression of PKD. Therefore, we investigated whether alternative TGF-ß superfamily ligands account for SMAD2/3 activation in cystic epithelial cells. Activins are members of the TGF-ß superfamily and drive SMAD2/3 phosphorylation via activin receptors, but activins have not been studied in the context of PKD. Mice with PKD had increased expression of activin ligands, even at early stages of disease. In addition, treatment with a soluble activin receptor IIB fusion (sActRIIB-Fc) protein, which acts as a soluble trap to sequester activin ligands, effectively inhibited cyst formation in three distinct mouse models of PKD. These data point to activin signaling as a key pathway in PKD and a promising target for therapy.


Subject(s)
Activins/antagonists & inhibitors , Polycystic Kidney Diseases/prevention & control , Signal Transduction , Animals , Disease Progression , Epithelial Cells , Female , Kidney/cytology , Male , Mice , Polycystic Kidney Diseases/etiology , Recombinant Fusion Proteins/pharmacology , Smad2 Protein/physiology , Smad3 Protein/physiology , Time Factors
8.
J Clin Invest ; 124(12): 5129-44, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25365220

ABSTRACT

The most severe form of autosomal dominant polycystic kidney disease occurs in patients with mutations in the gene (PKD1) encoding polycystin-1 (PC1). PC1 is a complex polytopic membrane protein expressed in cilia that undergoes autoproteolytic cleavage at a G protein-coupled receptor proteolytic site (GPS). A quarter of PKD1 mutations are missense variants, though it is not clear how these mutations promote disease. Here, we established a cell-based system to evaluate these mutations and determined that GPS cleavage is required for PC1 trafficking to cilia. A common feature among a subset of pathogenic missense mutations is a resulting failure of PC1 to traffic to cilia regardless of GPS cleavage. The application of our system also identified a missense mutation in the gene encoding polycystin-2 (PC2) that prevented this protein from properly trafficking to cilia. Using a Pkd1-BAC recombineering approach, we developed murine models to study the effects of these mutations and confirmed that only the cleaved form of PC1 exits the ER and can rescue the embryonically lethal Pkd1-null mutation. Additionally, steady-state expression levels of the intramembranous COOH-terminal fragment of cleaved PC1 required an intact interaction with PC2. The results of this study demonstrate that PC1 trafficking and expression require GPS cleavage and PC2 interaction, respectively, and provide a framework for functional assays to categorize the effects of missense mutations in polycystins.


Subject(s)
Polycystic Kidney Diseases/metabolism , TRPP Cation Channels/metabolism , Animals , Cell Line , Cilia/genetics , Cilia/metabolism , Cilia/pathology , Humans , Mice , Mice, Transgenic , Mutation, Missense , Polycystic Kidney Diseases/genetics , Polycystic Kidney Diseases/prevention & control , Protein Stability , Protein Structure, Tertiary , Protein Transport/genetics , TRPP Cation Channels/genetics
9.
Transplant Proc ; 41(9): 3639-41, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19917358

ABSTRACT

A pilot study was performed on adult polycystic kidney disease (PCKD) patients to examine the effects of the anti-proliferative mammalian target of rapamycin inhibitor sirolimus on the growth of renal cysts. Eight consecutive PCKD patients were given sirolimus (1 mg/d PO) for 6 consecutive months, in addition to an angiotensin receptor blocker (ARB), namely telmisartan. Another 8 PCKD patients served as a control group given only telmisartan. All PCKD patients had a serum creatinine value <2 mg/dL with a negative urine culture before enrollment. All patients were diagnosed by renal magnetic resonance imaging (MRI) to measure renal volumes. After a 6-month follow-up, patients were rescanned to remeasure the MRI volumes. Renal function was stable in 5/8 subjects in the sirolimus group, improved in 2 cases, and worsened in 1 with an increase of serum creatinine to >2 mg/dL resulting in his withdrawal after 5 months of follow-up. In contrast, the serum creatinine value was stable in 3 control group subjects, worsen in 3, and improved in 2. Four patients in the sirolimus group experienced infectious complications, namely, urinary tract infections (UTI) in 2 which were treated with antibiotics, and monilial pharyngitis in 2, who were treated and cured with a topical antifungal. In the control group, only 2 developed and were treated for UTIs. Hematologic tests were normal in all patients. There was an insignificant rise in kidney volume as measured by MRI in the sirolimus group (2845 vs 3221 mL after 6 months; P = NS) compared with a significant increase in the control group (2667 vs 3590 mL after 6 months; P < .05). We concluded that sirolimus, in addition to an ARB, might be beneficial for PCKD patients who present early in their illness.


Subject(s)
Polycystic Kidney Diseases/drug therapy , Sirolimus/therapeutic use , Adult , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Benzimidazoles/therapeutic use , Benzoates/therapeutic use , Blood Pressure , Creatinine/blood , Female , Glomerular Filtration Rate/drug effects , Humans , Immunosuppressive Agents/therapeutic use , Kidney/anatomy & histology , Kidney/drug effects , Magnetic Resonance Imaging , Male , Middle Aged , Pilot Projects , Polycystic Kidney Diseases/prevention & control , Telmisartan
11.
J Am Soc Nephrol ; 20(7): 1527-32, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19423689

ABSTRACT

In polycystic kidney disease (PKD), genetic mutations in polycystin 1 and 2 lead to defective intracellular trafficking of calcium, thereby decreasing intracellular calcium and altering cAMP signaling to favor proliferation. We hypothesized that calcimimetics, allosteric modulators of the calcium-sensing receptor, would reduce cyst growth by increasing intracellular calcium. We randomly assigned 20-wk-old male rats with a form of autosomal dominant PKD (heterozygote Cy/+) to one of four groups for 14 to 18 wk of treatment: (group 1) no treatment; (group 2) calcimimetic R-568 formulated in the diet; (group 3) R-568 plus calcium-supplemented drinking water (R-568 plus Ca); or (group 4) Ca-supplemented drinking water with a normal diet (Ca). Severity of PKD did not progress in any of the three treatment groups between 34 and 38 wk. Compared with no treatment, cyst growth was unaffected at 34 wk by all treatments, but cyst volume and fibrosis were lower at 38 wk, with both R-568-treated groups demonstrating a greater reduction than calcium alone. Between 34 and 38 wk, the total kidney weight increased by 78% in the control group (P < 0.001) and by 19% in the Ca group (P < 0.01), but did not increase in the R-568 or R-568 plus Ca groups, suggesting inhibition of disease progression despite equivalent suppression of parathyroid hormone. In summary, treatment of hyperparathyroidism halts late-stage progression of rodent cystic kidney disease. The benefit of R-568 alone suggests calcium-sensing receptor modulation may have additional inhibitory effects on late-stage cyst growth resulting from a direct modulation of intracellular calcium.


Subject(s)
Aniline Compounds/therapeutic use , Calcium/agonists , Polycystic Kidney Diseases/metabolism , Polycystic Kidney Diseases/prevention & control , Receptors, Calcium-Sensing/metabolism , Aniline Compounds/pharmacology , Animals , Calcium/metabolism , Disease Models, Animal , Disease Progression , Dose-Response Relationship, Drug , Fibrosis/metabolism , Fibrosis/pathology , Fibrosis/prevention & control , Hyperparathyroidism/etiology , Hyperparathyroidism/metabolism , Hyperparathyroidism/prevention & control , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Male , Parathyroid Hormone/metabolism , Phenethylamines , Polycystic Kidney Diseases/complications , Propylamines , Rats , Rats, Inbred Strains , Receptors, Calcium-Sensing/drug effects , Severity of Illness Index
12.
Nephron Exp Nephrol ; 110(2): e44-8, 2008.
Article in English | MEDLINE | ID: mdl-18776722

ABSTRACT

BACKGROUND/AIMS: Several dietary interventions, including those involving conjugated linoleic acid (CLA), slow progression of polycystic kidney disease (PKD) when initiated in the early stages of disease in Han:SPRD-cy rats. However, in humans, kidney disease is often undetected until extensive renal injury has developed. The objective of this study therefore was to determine whether initiating dietary CLA intervention in advanced PKD would slow disease progression. METHODS: Adult male Han:SPRD-cy rats with advanced kidney disease were fed diets with or without 1% CLA for 16 weeks. Disease progression was assessed by serum urea, proteinuria, and creatinine clearance, and morphological and immunohistochemical measurements for pathologic change. RESULTS: Renal injury was lower in the PKD rats given CLA compared to those given the control diet as indicated by a reduction in inflammation (42% less), fibrosis (28% less), oxidative damage (30% less) and proliferating cells (35% less). Diet had no effect on body, kidney, or liver weight, serum urea, serum creatinine, creatinine clearance, proteinuria, or cyst volume. CONCLUSIONS: Late dietary intervention with CLA reduced some disease-associated pathologies, but did not alter renal function in adult Han:SPRD-cy rats. The long-term anti-inflammatory, antioxidant, and antiproliferative benefits of CLA in advanced kidney disease remain to be determined.


Subject(s)
Linoleic Acids, Conjugated/administration & dosage , Polycystic Kidney Diseases/diet therapy , Polycystic Kidney Diseases/prevention & control , Animals , Disease Progression , Male , Rats
13.
Semin Fetal Neonatal Med ; 13(3): 118-24, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18543418

ABSTRACT

The demography of renal failure in childhood is examined through an analysis of the UK Renal Registry data on patients in established renal failure (ERF) and studies of chronic kidney disease populations. The predominant cause is renal dysplasia and related conditions. Congenital obstructive uropathy is the third largest group overall and the second in early childhood. Males predominate in both these groups. Antenatal diagnoses are frequently not made despite routine scanning. Those children, who present to nephrology after the age of 3 months without an antenatal diagnosis, progress to ERF later than those diagnosed antenatally. Discrepancies exist between the demography of antenatal diagnoses and those seen postnatally. This is likely to represent the limitations of antenatal ultrasound as a diagnostic screening tool.


Subject(s)
Kidney Diseases/epidemiology , Age of Onset , Child , Disease Progression , Female , Humans , Incidence , Male , Polycystic Kidney Diseases/epidemiology , Polycystic Kidney Diseases/prevention & control , Prevalence , Renal Insufficiency/epidemiology , Renal Insufficiency/ethnology , United Kingdom/epidemiology
14.
Proc Natl Acad Sci U S A ; 103(14): 5466-71, 2006 Apr 04.
Article in English | MEDLINE | ID: mdl-16567633

ABSTRACT

Autosomal-dominant polycystic kidney disease (ADPKD) is a common genetic disorder that frequently leads to renal failure. Mutations in polycystin-1 (PC1) underlie most cases of ADPKD, but the function of PC1 has remained poorly understood. No preventive treatment for this disease is available. Here, we show that the cytoplasmic tail of PC1 interacts with tuberin, and the mTOR pathway is inappropriately activated in cyst-lining epithelial cells in human ADPKD patients and mouse models. Rapamycin, an inhibitor of mTOR, is highly effective in reducing renal cystogenesis in two independent mouse models of PKD. Treatment of human ADPKD transplant-recipient patients with rapamycin results in a significant reduction in native polycystic kidney size. These results indicate that PC1 has an important function in the regulation of the mTOR pathway and that this pathway provides a target for medical therapy of ADPKD.


Subject(s)
Kidney/pathology , Polycystic Kidney Diseases/prevention & control , Protein Kinases/metabolism , Animals , Apoptosis/drug effects , Humans , Mice , Polycystic Kidney Diseases/pathology , Protein Kinases/drug effects , Sirolimus/pharmacology , TOR Serine-Threonine Kinases , TRPP Cation Channels
15.
Nephrol Ther ; 2 Suppl 2: S109-14, 2006 Jan.
Article in English | MEDLINE | ID: mdl-17373209

ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD) cystogenesis has been extensively studied and major characteristic abnormalities were identified including increased proliferation, apoptosis, changes in cellular polarity, abnormal matrix composition and fluid secretion. We set out to understand how mutated polycystin-1 leads to these abnormalities and how well mechanisms of cystogenesis in vivo can be understood using in vitro models. Specifically, we addressed the dynamic role of polycystin-1 in the context of cellular rearrangements accompanying cystogenesis and tubulogenesis in vitro. We demonstrated that polycystin-1 plays an important role in cell-cell adhesion through homophilic interactions of its Ig-like domains. To define the role of polycystin-1 in formation of intercellular contacts and cell polarity during epithelial morphogenesis, we have utilized a 3D MDCK in vitro model of tubulogenesis and cystogenesis. We demonstrate that polycystin-1 is a component of desmosomal junctions of epithelial cells. A striking down-regulation of polycystin-1 mRNA was detected in cysts as compared to tubules, leading to altered protein expression and localization. While polycystin-1 is localized to basolateral membranes of MDCK tubules, it is only detected in cytoplasmic pools in cystic cells. To address the impact of mutated PC-1 on intercellular adhesion, we have analyzed the structure/function of desmosomal junctions in primary cells derived from ADPKD cysts. We demonstrated that, in the absence of functional polycystin-1, desmosomal junctions can not be properly assembled and remain sequestered in cytoplasmic compartments. Our data show that the MDCK in vitro model of cystogenesis and tubulogenesis adequately reflects several aspects of cystogenesis in vivo. We have used in vitro cystogenesis assay for a high throughput screen of small molecule drugs and identified drugs specifically inhibiting cystogenesis but not tubulogenesis in vitro.


Subject(s)
Polycystic Kidney Diseases/prevention & control , Polycystic Kidney, Autosomal Dominant/genetics , TRPP Cation Channels/metabolism , Apoptosis , Cell Adhesion , Cell Division , Cell Polarity , Epithelial Cells/physiology , Gene Expression Regulation , Humans , Polycystic Kidney Diseases/genetics , Polycystic Kidney Diseases/pathology , Polycystic Kidney Diseases/physiopathology
16.
Lipids ; 41(12): 1141-9, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17269560

ABSTRACT

Flaxseed derivatives, including both oil and flax lignan, modify progression of renal injury in animal models, including Han:SPRD-cy polycystic kidney disease (PKD). Gender is a significant factor in the rates of progression of many forms of human renal disease, but the role of gender in the response to nutrition intervention in renal disease is unexplored. In this study, male and female Han:SPRD-cy rats or normal littermates were fed either corn oil (CO) or flax oil (FO) diets, with or without 20 mg/kg of the diet flax lignan secoisolaricinoresinol dyglycoside (SDG). Renal injury was assessed morphometrically and biochemically. Renal and hepatic PUFA composition was assessed by GC and renal PGE2 release by ELISA. FO preserved body weight in PKD males, with no effect in females. SDG reduced weight in both normal and PKD females. FO reduced proteinuria in both male and female PKD. FO reduced cystic change and renal inflammation in PKD males but reduced cystic change, fibrosis, renal inflammation, tissue lipid peroxides, and epithelial proliferation in PKD females. SDG reduced renal inflammation in all animals and lipid peroxides in PKD females. A strong interaction between SDG and FO was observed in renal FA composition of female kidneys only, suggesting increased conversion of C18 PUFA to C20 PUFA. FO reduced renal release of PGE2 in both genders. Gender influences the effects of flaxseed derivatives in Han:SPRD-cy rats. Gender-based responses to environmental factors, such as dietary lipid sources and micronutrients, may contribute to gender-based differences in disease progression rates.


Subject(s)
Flax/chemistry , Lignans/pharmacology , Linseed Oil/pharmacology , Polycystic Kidney Diseases/prevention & control , Animals , Corn Oil/administration & dosage , Corn Oil/pharmacology , Disease Models, Animal , Fatty Acids, Unsaturated/analysis , Fatty Acids, Unsaturated/metabolism , Female , Immunohistochemistry , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Kidney Function Tests , Lignans/administration & dosage , Lignans/chemistry , Linseed Oil/administration & dosage , Male , Phytotherapy , Polycystic Kidney Diseases/physiopathology , Prostaglandins E/metabolism , Rats , Sex Factors
18.
J Am Soc Nephrol ; 16(4): 846-51, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15728778

ABSTRACT

cAMP plays a major role in cystogenesis. Recent in vitro studies suggested that cAMP stimulates B-Raf/ERK activation and proliferation of cyst-derived cells in a Ca(2+) inhibitable, Ras-dependent manner. OPC-31260, a vasopressin V2 receptor (VPV2) antagonist, was shown to lower renal cAMP and inhibit renal disease development and progression in models orthologous to human cystic diseases. Here it is shown that OPC-41061, an antagonist chosen for its potency and selectivity for human VPV2, is effective in PCK rats. PCK kidneys have increased Ras-GTP and phosphorylated ERK levels and 95-kD/68-kD B-Raf ratios, changes that are corrected by the administration of OPC-31260 or OPC-41061. These results support the importance of cAMP in the pathogenesis of polycystic kidney disease, confirm the effectiveness of a VPV2 antagonist to be used in clinical trials for this disease, and suggest that OPC-31260 and OPC-41061 inhibit Ras/mitogen-activated protein kinase signaling in polycystic kidneys.


Subject(s)
Antidiuretic Hormone Receptor Antagonists , Benzazepines/pharmacology , Polycystic Kidney Diseases/prevention & control , Adenine , Animals , Cyclic AMP/metabolism , Disease Models, Animal , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Guanosine Triphosphate/metabolism , Introns/genetics , Kidney/metabolism , Male , Phosphorylation , Polycystic Kidney Diseases/genetics , Polycystic Kidney Diseases/metabolism , Polycystic Kidney, Autosomal Recessive/prevention & control , Proto-Oncogene Proteins B-raf/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Cell Surface/genetics , Thymine , Tolvaptan , ras Proteins/metabolism
19.
Kidney Int ; 64(5): 1573-9, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14531789

ABSTRACT

BACKGROUND: Increasing evidence supports an important role for the epidermal growth factor (EGF)/transforming growth factor-alpha (TGF-alpha)/EGF receptor (EGFR) axis in promoting tubular epithelial cell proliferation and cyst formation in polycystic kidney disease (PKD). METHODS: To determine whether the inhibition of EGFR tyrosine kinase activity can attenuate the development of PKD in the Han:SPRD rat, a frequently used animal model of autosomal-dominant slowly progressive PKD (ADPKD), wild-type and cy/+ rats were treated with EKI-785 or EKB-569 or with vehicle alone. Western analysis, immunoprecipitation, and immunohistochemistry were used to ascertain the expression, activation, and localization of EGFR. RESULTS: Overexpression, activation and apical mislocalization of EGFR were observed in the cy/+ rats. The intraperitoneal administration of EKI-785 reversed the activation of the EGFR to the level observed in wild-type animals. The intraperitoneal administration of EKI-785 (90 mg/kg body weight every third day) or of EKB-569 (20 mg/kg body weight every third day) to cy/+ rats resulted in lower kidney weights, serum concentrations of blood urea nitrogen (BUN), cyst volumes, and fibrosis scores. The administration of EKB-569 by gavage was less effective probably because of lower bioavailability. CONCLUSION: These results support a significant role for the EGF/TGF-alpha/EGFR axis in the development of PKD in the Han:SPRD rat and the therapeutic potential of EGFR tyrosine kinase inhibition in ADPKD.


Subject(s)
ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Polycystic Kidney Diseases/prevention & control , Quinazolines/pharmacology , Animals , Disease Models, Animal , Gastric Lavage , Injections, Intraperitoneal , Male , Polycystic Kidney Diseases/drug therapy , Rats , Rats, Sprague-Dawley
20.
Exp Nephrol ; 9(3): 171-80, 2001.
Article in English | MEDLINE | ID: mdl-11340301

ABSTRACT

Administration of ammonium chloride aggravates, while short-term administration of sodium or potassium bicarbonate lessens the development of polycystic kidney disease in Han:SPRD rats. We have conducted studies to determine whether the protection afforded by the administration of sodium bicarbonate is sustained and prevents development of uremia during chronic administration and whether the effects of the administration of ammonium chloride and sodium bicarbonate are also observed in a different model of polycystic kidney disease, the CD1-pcy/pcy mouse. We found that chronic administration of 200 mM sodium bicarbonate to Han:SPRD rats inhibited cystic enlargement and prevented the subsequent development of interstitial inflammation, chronic fibrosis, and uremia. We also found that, while the administration of ammonium chloride has similar effects in Han:SPRD rats and CD1-pcy/pcy mice, the administration of sodium bicarbonate is only protective in the Han:SPRD rats. This probably reflects differences in these models (predominately involvement of proximal tubules in Han:SPRD rats and of collecting ducts and distal tubules in pcy/pcy mice) and the different location and nature of the renal metabolic responses to the administration of acid or alkaline load.


Subject(s)
Ammonium Chloride/pharmacology , Polycystic Kidney Diseases/prevention & control , Sodium Bicarbonate/pharmacology , Ammonia/blood , Ammonia/metabolism , Ammonium Chloride/administration & dosage , Animals , Bicarbonates/blood , Bicarbonates/metabolism , Disease Models, Animal , Female , Fibrosis/prevention & control , Inflammation/prevention & control , Kidney/metabolism , Kidney/pathology , Male , Mice , Mice, Inbred Strains , Microscopy, Electron, Scanning , Organ Size/drug effects , Polycystic Kidney Diseases/metabolism , Polycystic Kidney Diseases/pathology , Rats , Rats, Inbred Strains , Sodium Bicarbonate/administration & dosage , Species Specificity , Time Factors , Uremia/prevention & control
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