transforming-growth-factor-beta and Polycystic-Kidney--Autosomal-Dominant

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by the progressive growth of cysts but it is also accompanied by diffuse tissue scarring or fibrosis. A number of recent studies have been published in this area, yet the role of fibrosis in ADPKD remains controversial. Here, we will discuss the stages of fibrosis progression in ADPKD, and how these compare with other common kidney diseases. We will also provide a detailed overview of some key mechanistic pathways to fibrosis in the polycystic kidney. Specifically, the role of the 'chronic hypoxia hypothesis', persistent inflammation, Transforming Growth Factor beta (TGFβ), Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) and microRNAs will be examined. Evidence for and against a pathogenic role of extracellular matrix during ADPKD disease progression will be provided.

Topics: Disease Progression; Fibrosis; Humans; Inflammation; Janus Kinases; Kidney; MicroRNAs; Polycystic Kidney, Autosomal Dominant; STAT Transcription Factors; Transforming Growth Factor beta

Initiation and progression of fluid filled cysts mark Autosomal Dominant Polycystic Kidney Disease (ADPKD). Thus, improved therapeutics targeting cystogenesis remains a constant challenge. Microarray studies in single ADPKD animal models species with limited sample sizes tend to provide scattered views on underlying ADPKD pathogenesis. Thus we aim to perform a cross species meta-analysis to profile conserved biological pathways that might be key targets for therapy.. Nine ADPKD microarray datasets on rat, mice and human fulfilled our study criteria and were chosen. Intra-species combined analysis was performed after considering removal of batch effect. Significantly enriched GO biological processes and KEGG pathways were computed and their overlap was observed. For the conserved pathways, biological modules and gene regulatory networks were observed. Additionally, Gene Set Enrichment Analysis (GSEA) using Molecular Signature Database (MSigDB) was performed for genes found in conserved pathways.. We obtained 28 modules of significantly enriched GO processes and 5 major functional categories from significantly enriched KEGG pathways conserved in human, mice and rats that in turn suggest a global transcriptomic perturbation affecting cyst - formation, growth and progression. Significantly enriched pathways obtained from up-regulated genes such as Genomic instability, Protein localization in ER and Insulin Resistance were found to regulate cyst formation and growth whereas cyst progression due to increased cell adhesion and inflammation was suggested by perturbations in Angiogenesis, TGF-beta, CAMs, and Infection related pathways. Additionally, networks revealed shared genes among pathways e.g. SMAD2 and SMAD7 in Endocytosis and TGF-beta.. Our study suggests cyst formation and progression to be an outcome of interplay between a set of several key deregulated pathways. Thus, further translational research is warranted focusing on developing a combinatorial therapeutic approach for ADPKD redressal.

Topics: Animals; Evolution, Molecular; Extracellular Matrix; Gene Expression Profiling; Humans; Mice; Polycystic Kidney, Autosomal Dominant; Rats; Smad Proteins; Transcriptome; Transforming Growth Factor beta

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited genetic disorder that is caused by mutations in

Topics: Animals; Cysts; Fibrosis; Histones; Kidney; Lysine; Methyltransferases; Mice; NIH 3T3 Cells; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Rats; Smad3 Protein; Transforming Growth Factor beta

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenetic inherited kidney disease characterized by renal progressive fluid-filled cysts and interstitial fibrosis. Inhibiting renal cyst development and interstitial fibrosis has been proven effective in delaying the progression of ADPKD. The purpose of this study was to discover effective drugs from natural products for preventing and treating ADPKD. Candidate compounds were screened from a natural product library by virtual screening. The Madin-Darby canine kidney (MDCK) cyst model, embryonic kidney cyst model, and orthologous mouse model of ADPKD were utilized to determine the pharmacological activities of the candidate compounds. Western blot and morphological analysis were used to investigate underlying mechanisms. The experimental results showed that 0.625, 2.5, and 10 μM cardamonin dose-dependently reduced formation and enlargement in MDCK cyst model. Cardamonin also significantly attenuated renal cyst enlargement in ex vivo mouse embryonic kidneys and PKD mouse kidneys. We found that cardamonin inhibited renal cyst development and interstitial fibrosis by downregulating the MAPK, Wnt, mTOR, and transforming growth factor-β/Smad2/3 signaling pathways. Cardamonin significantly inhibits renal cyst development and interstitial fibrosis, suggesting that cardamonin shows promise as a potential therapeutic drug for preventing and treating ADPKD.

Topics: Animals; Chalcones; Cysts; Dogs; Female; Fibrosis; Kidney; Madin Darby Canine Kidney Cells; Mice, Inbred ICR; Mice, Transgenic; Mitogen-Activated Protein Kinases; Polycystic Kidney, Autosomal Dominant; Signal Transduction; Smad2 Protein; Smad3 Protein; TOR Serine-Threonine Kinases; Transforming Growth Factor beta

Renal cyst enlargement is associated with the activation of both the circulating and intrarenal renin-angiotensin systems. Angiotensinogen (AGT) is the substrate for renin. The aim of the present study was to determine the effect of AGT inhibition on renal cyst enlargement. An AGT antisense oligonucleotide (ASO) that selectively inhibits AGT mRNA was injected once weekly in PKD2WS25 mice [an orthologous model of human autosmal dominant polycystic kidney disease (PKD) involving mutation of the Pkd2 gene] from 4 to 16 wk of age. The AGT ASO resulted in a 40% decrease in AGT RNA in the kidney, a 60% decrease in AGT RNA in the liver, and a significant decrease in AGT protein in the kidney and serum. The AGT ASO resulted in a significant decrease in kidney size, cyst volume density, and blood urea nitrogen. The AGT ASO resulted in a significant decrease in transforming growth factor-β and interstitial fibrosis in the kidney. Mice treated with the AGT ASO had a significant decrease in proinflammatory cytokines [chemokine (C-X-C motif) ligand (CXCL)1 and IL-12] in the kidney. Cluster of differentiation (CD)36 is a scavenger receptor found on tubular cells that can activate the renin-angiotensin system. Administration of a CD36 ASO had no effect on PKD and kidney function, suggesting that the effect of the AGT ASO is independent of CD36. In summary, AGT inhibition resulted in significant decreases in kidney size and cyst volume and an improvement in kidney function in PKD mice. The AGT ASO resulted in a decrease in transforming growth factor-β, interstitial fibrosis, and the proinflammatory cytokines CXCL1 and IL-12 in the kidney.

Topics: Angiotensinogen; Animals; Blood Urea Nitrogen; CD36 Antigens; Cells, Cultured; Chemokine CXCL1; Disease Models, Animal; Down-Regulation; Female; Fibrosis; Genetic Therapy; Interleukin-12; Kidney; Male; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Oligonucleotides, Antisense; Polycystic Kidney, Autosomal Dominant; Recovery of Function; RNA, Messenger; Transforming Growth Factor beta; TRPP Cation Channels

Current assessment tools of autosomal dominant polycystic kidney disease (ADPKD) diagnosis are challenging. This study evaluated the possible application of assessment of interleukin (IL)-17-related cytokines and the circulatory T helper 17 cells in the diagnosis of ADPKD.. Enrolling 54 ADPKD patients and 54 healthy individuals, we measured serum and urine levels of IL-6, IL-17, IL-23, and transforming growth factor-β and the peripheral blood frequency of T helper 17 cells through flowcytometry. We computed sensitivity and specificity of each inflammatory marker as well as their different combinations using the receiver operating characteristic curve and discriminant function analysis.. The mean serum and urine levels of IL-17 and IL-23 as well as urine levels of IL-6 were higher in ADPKD patients compared to the healthy controls (P < .001). There was no significant difference in the number of T helper 17 cells between the two groups. Among different combinations of the inflammatory markers, the serum IL-17 was the best factor in the diagnosis of ADPKD with a sensitivity as well as specificity of 100%.. It is likely that T helper 17 pathway is involved in the pathogenesis of ADPKD; therefore, it may be beneficial if such a pathway be considered in its diagnosis.

Topics: Adult; Biomarkers; Case-Control Studies; Disease Progression; Female; Flow Cytometry; Humans; Interleukin-17; Interleukin-23; Interleukin-6; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Th17 Cells; Transforming Growth Factor beta

Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of renal failure that is due to mutations in two genes, PKD1 and PKD2. Vascular complications, including aneurysms, are a well recognized feature of ADPKD, and a subgroup of families exhibits traits reminiscent of Marfan syndrome (MFS). MFS is caused by mutations in fibrillin-1 (FBN1), which encodes an extracellular matrix protein with homology to latent TGF-β binding proteins. It was recently demonstrated that fibrillin-1 deficiency is associated with upregulation of TGF-β signaling. We investigated the overlap between ADPKD and MFS by breeding mice with targeted mutations in Pkd1 and Fbn1. Double heterozygotes displayed an exacerbation of the typical Fbn1 heterozygous aortic phenotype. We show that the basis of this genetic interaction results from further upregulation of TGF-β signaling caused by Pkd1 haploinsufficiency. In addition, we demonstrate that loss of PKD1 alone is sufficient to induce a heightened responsiveness to TGF-β. Our data link the interaction of two important diseases to a fundamental signaling pathway.

Topics: Animals; Disease Models, Animal; Epistasis, Genetic; Female; Fibrillin-1; Fibrillins; Genetic Association Studies; Haploinsufficiency; Heterozygote; Humans; Male; Marfan Syndrome; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Microfilament Proteins; Mutation; Polycystic Kidney, Autosomal Dominant; Signal Transduction; Transforming Growth Factor beta; TRPP Cation Channels; Vascular Diseases

Topics: Animals; Female; Humans; Male; Microfilament Proteins; Polycystic Kidney, Autosomal Dominant; Transforming Growth Factor beta; TRPP Cation Channels; Vascular Diseases

Recent studies have showed that epithelial-mesenchymal transition (EMT) is a key process of glomerular and tubulointerstitial pathology in many chronic kidney diseases. However, there are no data of EMT in humane autosomal dominant polycystic kidney disease (ADPKD).. ADPKD kidneys (N = 5) with end stage renal disease (ESRD) and control kidneys (N = 4) were analyzed immnunohistochemically. We evaluated alpha-SMA, E-cadherin, vimentin, TGF-beta1 and Smad 2/3 expression in ADPKD and compared them with those in control kidney. These immunohistochemical findings were quantitatively analyzed by computer-assisted image analyzer and positive tubules (%).. There were severe interstitial fibrosis and proliferation of alpha-SMA+ myofibroblasts in ADPKD. Cystic tubular epithelial cells in ADPKD lost epithelial marker (E-cadherin) and expressed mesenchymal markers (alpha-SMA, vimentin). There were significant increases of alpha-SMA (34.3 +/- 11.7% vs 0.9 +/- 1.5%), vimentin (19.9 +/- 3.9% vs 3.3 +/- 1.4%), TGF-beta1 (5.42 +/- 2.83% vs 0%) and Smad 2/3 (3.4 +/- 1.7% vs 0.7 +/- 0.6%) in ADPKD kidneys compared with control kidneys evidenced by computer-assisted image analyzer. When we analyze the positive tubules (%), the results were the same as computer-assisted image analyzer.. Our results showed that the end stage of ADPKD is associated with TGF-beta, Smad 2/3 and markers of EMT. It suggests that TGF-beta mediated EMT has a role in progression of ADPKD.

Topics: Aged; Biomarkers; Cell Division; Disease Progression; Epithelial Cells; Female; Fibrosis; Humans; Kidney Glomerulus; Kidney Tubules; Male; Mesoderm; Middle Aged; Polycystic Kidney, Autosomal Dominant; Transforming Growth Factor beta

Progressive renal enlargement due to the growth of innumerable fluid-filled cysts is a central pathophysiological feature of autosomal dominant polycystic kidney disease (ADPKD). These epithelial neoplasms enlarge slowly and damage noncystic parenchyma by mechanisms that have not been clearly defined. In a microarray analysis of cultured human ADPKD cyst epithelial cells, periostin mRNA was overexpressed 15-fold compared with normal human kidney (NHK) cells. Periostin, initially identified in osteoblasts, is not expressed in normal adult kidneys but is expressed transiently during renal development. We found periostin in cyst-lining cells in situ in the extracellular matrix adjacent to the cysts and within cyst fluid. ADPKD cells secreted periostin across luminal and basolateral plasma membranes. Periostin increased proliferation of cyst epithelial cells 27.9 +/- 3.1% (P < 0.001) above baseline and augmented in vitro cyst growth but did not affect proliferation of normal renal cells. Expression of alphaV-integrin, a periostin receptor, was ninefold higher in ADPKD cells compared with NHK cells, and antibodies that block alphaV-integrin inhibited periostin-induced cell proliferation. We conclude that periostin is a novel autocrine mitogen secreted by mural epithelial cells with the potential to accelerate cyst growth and promote interstitial remodeling in ADPKD.

Topics: Antibodies; Cell Adhesion Molecules; Cell Cycle; Cell Proliferation; Cells, Cultured; Colforsin; Cyclic AMP; Cyst Fluid; Cysts; Epidermal Growth Factor; Epithelial Cells; Extracellular Matrix; Flow Cytometry; Gene Expression; Humans; Immunohistochemistry; Integrin alphaV; Kidney; Polycystic Kidney, Autosomal Dominant; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta

Progression of autosomal-dominant polycystic kidney disease (ADPKD) in the heterozygous male Han:SPRD rat is dramatically slowed by ingestion of potassium or sodium citrate. This study examined the efficacy of delayed therapy with sodium citrate, the effect of sodium citrate therapy on kidney cortex levels of transforming growth factor-beta (TGF-beta), and the response to calcium citrate ingestion. Rats were provided with citrate salts in their food, and renal clearance, blood pressure, blood chemistry, and survival determinations were made. Sodium citrate therapy was most effective when started at age 1 month, and delay of therapy until age 3 months produced no benefit. Kidney cortex TGF-beta levels were elevated in 3- and 8-month-old rats with ADPKD, but not in 6-week-old rats. Sodium citrate treatment, started at age 1 month, lowered TGF-beta levels to normal in 3-month-old rats, but this is probably not the primary mechanism of citrate's beneficial effect. Calcium citrate had only a modest effect in preserving glomerular filtration rate. Effective treatment of ADPKD in this rat model requires early administration of a readily absorbed alkalinizing citrate salt. Existing data on ADPKD patients on vegetarian diets or with kidney stones should be studied in light of these findings.

Topics: Animals; Animals, Congenic; Calcium; Calcium Citrate; Citrates; Creatinine; Disease Models, Animal; Glomerular Filtration Rate; Hydrogen-Ion Concentration; Kidney Cortex; Male; Polycystic Kidney, Autosomal Dominant; Rats; Rats, Sprague-Dawley; Sodium Citrate; Transforming Growth Factor beta; Urea; Urine

Two genetic loci, PKD I and PKD2, have been identified as being responsible for ADPKD, and PKD1 is known to be associated with a poor prognosis. However, the presence of an intrafamilial study clinical diversity suggests that there are disease-modifying loci. Because the mechanism ofthe renal failure in ADPKD includes a cystic growth and tubulointerstitial atrophy and fibrosis, we studied the associations between 2 polymorphisms in the TGF-beta1 gene, which are known to be associated with chronic tubulointerstitial inflammation, and ADPKD progression in Korean patients.. One hundred and twenty-five individuals who had ADPKD and 47 normal control subjects were genotyped by PCR-RFLP, the T869C (Leu10Pro) variant of TGF-beta gene leader sequence was discriminated with MspA1I and the G915C (Arg25Pro) variants with Bg1I. Statistical significances were determined using the Chi-square test.. The distribution of the alleles for the TGF beta1 Leu10Pro polymorphism in ADPKD was: T 54%, C 46%, which was similar to the Korean (56: 44, p = 0.887) and Western controls (65: 35). In addition, no differences were found between the ESRD and the non-ESRD groups (p = 0.888) or the early hypertension and the normotension groups (p = 0.249). The distribution of alleles for the TGF beta1 Arg25Pro polymorphism showed only the GG type which was different from the Western population controls (G:C = 90:10, p = 0.000).. Our results suggest that the polymorphism at Arg25Pro of TGF-beta1 in the Korean population has an allele distribution different from that ofthe Western population and that the polymorphism at Leu10Pro of TGF-beta1 has no association with the renal progression in Korean ADPKD patients.

Topics: Adult; Aged; Disease Progression; Female; Gene Frequency; Humans; Kidney Failure, Chronic; Korea; Male; Membrane Proteins; Middle Aged; Polycystic Kidney, Autosomal Dominant; Polymorphism, Genetic; Proteins; Transforming Growth Factor beta; Transforming Growth Factor beta1; TRPP Cation Channels

The vascular hallmark of chronic rejection (CR), as well as of atherosclerosis, is initial hyperplasia. It results from migration and proliferation of vascular smooth muscle cell and increased deposition of extracellular matrix proteins. A possible mechanism responsible for formation of neointima is the release of growth factors and cytokines, such as: transforming growth factor beta (TGF-beta), tumour necrosis factor alfa (TNF-alpha), interleukin 1 (IL-1) and interleukin 6 (IL-6). The expression of these factors in the renal artery wall of chronically rejected allografts was quantified. The renal artery samples were obtained from patients with chronic renal allograft rejection, undergoing graftectomy (n = 11) and patients with autosomal dominant polycystic kidney disease (ADPKD), undergoing nephrectomy (n = 4). Total RNA was isolated and the expression of mRNA for TGF-beta, TNF-alpha, IL-1 and IL-6 was measured using a real time PCR. In patients with CR the expression levels of TGF-beta, TNF-alpha and IL-1 mRNA were higher than in control group. No difference between groups was detected for IL-6. In both groups a correlation was detected between age and TGF-beta expression. The increased expression of TGF-beta, TNF-alpha and IL-1 may be a key factor in the neointimal formation and pathogenesis of CR. The increase in the TGF-b expression with age might be a protective mechanism in atherosclerosis.

Topics: Adult; Aged; Case-Control Studies; Cytokines; Female; Gene Expression; Graft Rejection; Growth Substances; Humans; Hyperplasia; Interleukin-1; Interleukin-6; Kidney Transplantation; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Polymerase Chain Reaction; Renal Artery; RNA, Messenger; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The expansion of cysts in polycystic kidneys bears several similarities to the invasion of the extracellular matrix by benign tumors. We therefore hypothesized that cyst-lining epithelial cells produce extracellular matrix-degrading metalloproteinases and that the inhibition of these enzymes may represent a potential target for therapeutic intervention. Using in situ hybridization, we first analyzed the expression of membrane-type metalloproteinase 1 (MMP-14), an essential matrix metalloproteinase, of its inhibitor TIMP-2, and of the cytokine transforming growth factor (TGF)-beta2 in the (cy/+) rat model of autosomal-dominant polycystic kidney disease. Upregulated MMP-14 mRNA was predominantly located in cyst-lining epithelia and distal tubules, whereas TIMP-2 mRNA was confined almost exclusively to fibroblasts. TGF-beta2, a cytokine known to regulate the expression of matrix metalloproteinases and their inhibitors, was also expressed by cyst wall epithelia. We then treated (cy/+) rats with the metalloproteinase inhibitor batimastat for a period of 8 wk. The treatment with the metalloproteinase inhibitor batimastat resulted in a significant reduction of cyst number and kidney weight. Our study suggests that metalloproteinase inhibitors represent a new therapeutic tool against polycystic kidney disease, which should be applicable independently of the background of the disease.

Topics: Animals; Disease Models, Animal; Kidney; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases; Phenylalanine; Polycystic Kidney, Autosomal Dominant; Protease Inhibitors; Rats; Rats, Inbred Strains; RNA, Messenger; Thiophenes; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta; Transforming Growth Factor beta2

Topics: Cells, Cultured; Collagen; Extracellular Matrix; Fibroblast Growth Factor 2; Humans; Polycystic Kidney, Autosomal Dominant; Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta

Autosomal dominant polycystic kidney disease (ADPKD) is the most common entity of cystic diseases of the kidney leading to end-stage renal insufficiency. Changes in extracellular matrix (ECM) are regarded to be an important pathogenic factor connected with the genes assumed to be responsible for human ADPKD. In order to assess the biological significance of altered expression and deposition of ECM glycoproteins for human ADPKD at molecular levels fresh-frozen tissue from ADPKD kidneys, fetal kidneys and normal adult kidneys were comparatively tested by immunohistochemistry for the presence of multifunctional ECM glycoproteins undulin, tenascin and fibronectin, interstitial collagen types I, III and VI and intrinsic basement membrane components laminin and collagen type IV using monoclonal antibodies and polyclonal antisera. Studies were especially focused on ECM glycoproteins undulin and tenascin which in connection with interstitial collagens and fibronectin have specific structural and functional roles in tissue development and differentiation. Cultures of cyst-lining epithelial cells from two polycystic kidneys and autologous fibroblasts were investigated in vitro. By Northern blot analysis mRNA levels of undulin, tenascin and the ECM-regulating growth factor transforming growth factor-beta 1 (TGF-beta 1) were investigated. A strong increase of fibrogenesis was demonstrated in tissue architecture of polycystic kidneys. Immunohistochemically subepithelial fibrous tissue of cyst walls in ADPKD kidneys showed strong coexpression of both undulin and tenascin with marked intensity adjacent to cyst-lining epithelium. In contrast the normal adult human kidney and developmental stages of the fetal kidney showed expression patterns of undulin and tenascin which were significantly different.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Cell Adhesion Molecules, Neuronal; Cells, Cultured; Collagen; Extracellular Matrix Proteins; Fetus; Fibronectins; Gene Expression; Glycoproteins; Humans; Immunohistochemistry; Kidney; Laminin; Polycystic Kidney, Autosomal Dominant; RNA, Messenger; Tenascin; Transforming Growth Factor beta

The DBA/2FG-pcy mouse has a form of slowly progressive kidney disease that appears similar in many respects to that seen in the autosomal dominant form of human polycystic kidney disease. The aim of this study was to examine the mRNA expression of growth-related proteins in kidney obtained from DBA/2FG-pcy mice and control DBA/2 mice at 8, 16, and 30 wk of age. The mRNA levels encoding for proliferating cell nuclear antigen (PCNA), transforming growth factor (TGF)-beta, platelet-derived growth factor (PDGF)-A and PDGF-B chains, insulin-like growth factor (IGF)-I, and basic fibroblast growth factor (bFGF) were increased with the progression of cystic lesions in the kidneys of DBA/2FG-pcy mice. At 30 wk of age, mRNA levels of PCNA, TGF-beta, PDGF-A and PDGF-B chains, IGF-I, and bFGF were increased 5.4-fold, 4.8-fold, 4.4-fold, 3.8-fold, 3.7-fold, and 4.6-fold, respectively, compared with those of control DBA/2 mice. In contrast, mRNA levels for epidermal growth factor in kidney of DBA/2FG-pcy mice decreased with age as compared with those of DBA/2 mice. These results suggest that decreased epidermal growth factor mRNA expression and increased expression of PCNA, TGF-beta, PDGF-A and PDGF-B chains, IGF-I, and bFGF mRNA may contribute to the progression of cystic lesions in DBA/2FG-pcy mice.

Topics: Age Factors; Animals; DNA Probes; Fibroblast Growth Factor 2; Gene Expression; Growth Substances; Insulin-Like Growth Factor I; Kidney; Mice; Mice, Inbred DBA; Mice, Mutant Strains; Nuclear Proteins; Platelet-Derived Growth Factor; Polycystic Kidney, Autosomal Dominant; Proliferating Cell Nuclear Antigen; RNA, Messenger; Transforming Growth Factor beta