Unique interstitial miRNA signature drives fibrosis in a murine model of autosomal dominant polycystic kidney disease.

Aim: To delineate changes in miRNA expression localized to the peri-cystic local microenvironment (PLM) in an orthologous mouse model of autosomal dominant polycystic kidney disease (ADPKD) ( ).

Methods: We profiled miRNA expression in the whole kidney and laser captured microdissection (LCM) samples from PLM in kidneys with Qiagen miScript 384 HC miRNA PCR arrays. The three times points used are: (1) post-natal (PN) day 21, before the development of trichrome-positive areas; (2) PN28, the earliest sign of trichrome staining; and (3) PN42 following the development of progressive fibrosis.

Tesevatinib ameliorates progression of polycystic kidney disease in rodent models of autosomal recessive polycystic kidney disease.

Aim: To investigate the therapeutic potential of tesevatinib (TSV), a unique multi-kinase inhibitor currently in Phase II clinical trials for autosomal dominant polycystic kidney disease (ADPKD), in well-defined rodent models of autosomal recessive polycystic kidney disease (ARPKD).

Methods: We administered TSV in daily doses of 7.5 and 15 mg/kg per day by I.

Emerging Therapies for Childhood Polycystic Kidney Disease.

Cystic kidney diseases comprise a varied collection of hereditary disorders, where renal cysts comprise a major element of their pleiotropic phenotype. In pediatric patients, the term polycystic kidney disease (PKD) commonly refers to two specific hereditary diseases, autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD). Remarkable progress has been made in understanding the complex molecular and cellular mechanisms of renal cyst formation in ARPKD and ADPKD.

Pathophysiology of childhood polycystic kidney diseases: new insights into disease-specific therapy.

Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are significant causes of morbidity and mortality in children and young adults. ADPKD, with an incidence of 1:400 to 1:1,000, affects more than 13 million individuals worldwide and is a major cause of end-stage renal disease in adults. However, symptomatic disease is increasingly recognized in children.

Smac-mimetic-induced epithelial cell death reduces the growth of renal cysts.

Past efforts to pharmacologically disrupt the development and growth of renal cystic lesions focused primarily on normalizing the activity of a specific signaling molecule, but the effects of stimulating apoptosis in the proliferating epithelial cells have not been well studied. Although benign, ADPKD renal cysts created by the sustained proliferation of epithelial cells resemble tumors, and malignant cell death can be achieved by cotreatment with TNF-α and a mimetic of second mitochondria-derived activator of caspase (Smac). Notably, TNF-α accumulates to high levels in ADPKD cyst fluid.

Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease.

Autosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2 and is characterized by the development of multiple bilateral renal cysts that replace normal kidney tissue. Here, we used Pkd1 mutant mouse models to demonstrate that the nicotinamide adenine dinucleotide-dependent (NAD-dependent) protein deacetylase sirtuin 1 (SIRT1) is involved in the pathophysiology of ADPKD. SIRT1 was upregulated through c-MYC in embryonic and postnatal Pkd1-mutant mouse renal epithelial cells and tissues and could be induced by TNF-α, which is present in cyst fluid during cyst development.

New approaches to the autosomal recessive polycystic kidney disease patient with dual kidney-liver complications.

Improved neonatal medical care and renal replacement technology have improved the long-term survival of patients with ARPKD. Ten-yr survival of those surviving the first year of life is reported to be 82% and is continuing to improve further. However, despite increases in overall survival and improved treatment of systemic hypertension and other complications of their renal disease, nearly 50% of survivors will develop ESRD within the first decade of life.

G-protein signaling modulator 1 deficiency accelerates cystic disease in an orthologous mouse model of autosomal dominant polycystic kidney disease.

Polycystic kidney diseases are the most common genetic diseases that affect the kidney. There remains a paucity of information regarding mechanisms by which G proteins are regulated in the context of polycystic kidney disease to promote abnormal epithelial cell expansion and cystogenesis. In this study, we describe a functional role for the accessory protein, G-protein signaling modulator 1 (GPSM1), also known as activator of G-protein signaling 3, to act as a modulator of cyst progression in an orthologous mouse model of autosomal dominant polycystic kidney disease (ADPKD).

HDAC6 regulates epidermal growth factor receptor (EGFR) endocytic trafficking and degradation in renal epithelial cells.

We present for the first time that histone deacetylase 6 (HDAC6) regulates EGFR degradation and trafficking along microtubules in Pkd1 mutant renal epithelial cells. HDAC6, the microtubule-associated α-tubulin deacetylase, demonstrates increased expression and activity in Pkd1 mutant mouse embryonic kidney cells. Targeting HDAC6 with a general HDAC inhibitor, trichostatin (TSA), or a specific HDAC6 inhibitor, tubacin, increased the acetylation of α-tubulin and downregulated the expression of EGFR in Pkd1 mutant renal epithelial cells.

Role of genetic modifiers in an orthologous rat model of ARPKD.

Human data and animal models of autosomal recessive polycystic kidney disease (ARPKD) suggest that genetic factors modulate the onset and severity of the disease. We report here for the first time that ARPKD susceptibility is attenuated by introgressing the mutated Pkhd1 disease allele from the polycystic kidney (PCK) rat onto the FHH (Fawn-Hooded Hypertensive) genetic background. Compared with PCK, the FHH.

Loss of activator of G-protein signaling 3 impairs renal tubular regeneration following acute kidney injury in rodents.

The intracellular mechanisms underlying renal tubular epithelial cell proliferation and tubular repair following ischemia-reperfusion injury (IRI) remain poorly understood. In this report, we demonstrate that activator of G-protein signaling 3 (AGS3), an unconventional receptor-independent regulator of heterotrimeric G-protein function, influences renal tubular regeneration following IRI. In rat kidneys exposed to IRI, there was a temporal induction in renal AGS3 protein expression that peaked 72 h after reperfusion and corresponded to the repair and recovery phase following ischemic injury.

Diagnosis and management of childhood polycystic kidney disease.

A number of syndromic disorders have renal cysts as a component of their phenotypes. These disorders can generally be distinguished from autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) by imaging studies of their characteristic, predominantly non-renal associated abnormalities. Therefore, a major distinction in the differential diagnosis of enlarge echogenic kidneys is delineating ARPKD from ADPKD.

Birth of a healthy infant following preimplantation PKHD1 haplotyping for autosomal recessive polycystic kidney disease using multiple displacement amplification.

Purpose: To develop a reliable preimplantation genetic diagnosis protocol for couples who both carry a mutant PKHD1 gene wishing to conceive children unaffected with autosomal recessive polycystic kidney disease (ARPKD).

Methods: Development of a unique protocol for preimplantation genetic testing using whole genome amplification of single blastomeres by multiple displacement amplification (MDA), and haplotype analysis with novel short tandem repeat (STR) markers from the PKHD1 gene and flanking sequences, and a case report of successful utilization of the protocol followed by successful IVF resulting in the birth of an infant unaffected with ARPKD.

Results: We have developed 20 polymorphic STR markers suitable for linkage analysis of ARPKD.

20-HETE activates the Raf/MEK/ERK pathway in renal epithelial cells through an EGFR- and c-Src-dependent mechanism.

20-Hydroxyeicosatetraenoic acid (20-HETE) has been reported to promote mitogenicity in a variety of cell types, including renal epithelial cells. However, the signal transduction pathways activated by 20-HETE have not been fully defined. The present study evaluated the effects of 20-HETE and its more stable agonist analogs 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (5,14-20-HEDE) and N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5,14-20-HEDGE) on the Raf/MEK/ERK and phosphatidylinositol 3-kinase (PI3K)-Akt pathway in LLC-PK(1) renal epithelial cells.

Chronic blockade of 20-HETE synthesis reduces polycystic kidney disease in an orthologous rat model of ARPKD.

20-Hydroxyeicosatetraenoic acid (20-HETE) has been implicated as a potential mediator in epithelial cell proliferation and cyst formation in polycystic kidney disease (PKD). In the present study, we studied the effects of chronic blockade of 20-HETE synthesis in an orthologous rodent model of autosomal recessive polycystic kidney disease (ARPKD), the PCK rat. RT-PCR analysis indicated that the expression of CYP4A1, CYP4A2, CYP4A3, and CYP4A8 mRNA was increased two- to fourfold in cystic PCK compared with noncystic Sprague-Dawley rat kidneys.

20-HETE mediates proliferation of renal epithelial cells in polycystic kidney disease.

Polycystic kidney diseases are characterized by abnormal proliferation of renal epithelial cells. In this study, the role of 20-hydroxyeicosatetraenoic acid (20-HETE), an endogenous cytochrome P450 metabolite of arachidonic acid with mitogenic properties, was evaluated in cystic renal disease. Daily administration of HET-0016, an inhibitor of 20-HETE synthesis, significantly reduced kidney size by half in the BPK mouse model of autosomal recessive polycystic kidney disease.

Src inhibition ameliorates polycystic kidney disease.

Despite identification of the genes responsible for autosomal dominant polycystic kidney disease (PKD) and autosomal recessive PKD (ARPKD), the precise functions of their cystoprotein products remain unknown. Recent data suggested that multimeric cystoprotein complexes initiate aberrant signaling cascades in PKD, and common components of these signaling pathways may be therapeutic targets. This study identified c-Src (pp60(c-Src)) as one such common signaling intermediate and sought to determine whether Src activity plays a role in cyst formation.

Renal cystic disease: new insights for the clinician.

This article cannot comprehensively cover the enormous strides made in defining the molecular and cellular basis of renal cystic diseases over the last decade. Therefore, it provides a brief overview and categorization of inherited, developmental, and acquired renal cystic diseases, providing a relevant, up-to-date bibliography as well as a useful list of informative Internet Web sites. Its major focus is the translational biology of polycystic kidney disease.

Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis: summary statement of a first National Institutes of Health/Office of Rare Diseases conference.

Researchers and clinicians with expertise in autosomal recessive polycystic kidney disease and congenital hepatic fibrosis (ARPKD/CHF) and related fields met on May 5-6, 2005, on the National Institutes of Health (NIH) campus for a 1.5-day symposium sponsored by the NIH Office of Rare Diseases, the National Human Genome Research Institute (NHGRI), and in part by the ARPKD/CHF Alliance. The meeting addressed the present status and the future of ARPKD/CHF research.

Molecular and cellular pathophysiology of autosomal recessive polycystic kidney disease (ARPKD).

Autosomal recessive polycystic kidney disease (ARPKD) belongs to a group of congenital hepatorenal fibrocystic syndromes characterized by dual renal and hepatic involvement of variable severity. Despite the wide clinical spectrum of ARPKD (MIM 263200), genetic linkage studies indicate that mutations at a single locus, PKHD1 (polycystic kidney and hepatic disease 1), located on human chromosome region 6p21.1-p12, are responsible for all phenotypes of ARPKD.

Haplotype analysis improves molecular diagnostics of autosomal recessive polycystic kidney disease.

Background: Autosomal recessive polycystic kidney disease (ARPKD) is characterized by wide phenotypic variability, ranging from in utero detection with enlarged, echogenic kidneys to an adult presentation with congenital hepatic fibrosis. The ARPKD gene, PKHD1 , covers about 470 kb of DNA (67 exons), and mutation studies have found marked allelic heterogeneity with a high level of novel missense changes and neutral polymorphisms. To improve the prospects for molecular diagnostics and to study the origin of some relatively common mutations, the authors have developed a strategy for improved ARPKD haplotyping.

Epidermal growth factor receptor tyrosine kinase inhibition is not protective in PCK rats.

Background: Advances in the understanding of cystogenesis, identification of the PKHD1 gene and availability of a rat model (the PCK rat) caused by a Pkhd1 mutation facilitate testing of therapies for autosomal-recessive polycystic kidney disease (ARPKD). Considerable support exists for the importance of the epidermal growth factor (EGF)/transforming growth factor-alpha (TGF-alpha)/EGF receptor (EGFR) axis and of the adenylyl cyclase-adenosine 3',5'-cyclic monophosphate (cAMP) pathway in the pathogenesis of cyst formation and progressive enlargement.

Methods: To determine whether EGFR tyrosine kinase inhibition is protective in the PCK rat, male and female animals were treated with EKI-785 or EKB-569 or with vehicle alone between 3 and 10 weeks of age.

EGF-related growth factors in the pathogenesis of murine ARPKD.

Background: Epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha) and their receptor, EGFR, play key roles in polycystic kidney disease (PKD) pathogenesis. Renal expression of two related growth factors, amphiregulin and heparin-binding EGF, has not been examined previously in PKD. The aims of this study of murine autosomal-recessive polycystic kidney disease (ARPKD) were (1) to characterize amphiregulin and heparin-binding EGF expression in cystic versus normal kidneys and cells; and (2) to identify the functional effects of abnormal EGF-related growth factor expression.