scholarly journals Loss of Tsc1, but not Pten, in renal tubular cells causes polycystic kidney disease by activating mTORC1

2009 ◽  
Vol 18 (22) ◽  
pp. 4428-4441 ◽  
Author(s):  
Jing Zhou ◽  
James Brugarolas ◽  
Luis F. Parada
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Polycystic Kidney ◽  
Tubular Cells ◽  
Renal Tubular Cells ◽  
Renal Tubular

scholarly journals The cellular pathways and potential therapeutics of Polycystic Kidney Disease

2021 ◽  
Author(s):  
Taylor Richards ◽  
Kavindiya Modarage ◽  
Soniya A. Malik ◽  
Paraskevi Goggolidou
Keyword(s):  
Clinical Trials ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Cellular Proliferation ◽  
Cyst Formation ◽  
Great Promise ◽  
Polycystic Kidney ◽  
Renal Tubular Cells ◽  
Renal Tubular ◽  
Stage Renal Disease

Polycystic Kidney Disease (PKD) refers to a group of disorders, driven by the formation of cysts in renal tubular cells and is currently one of the leading causes of end-stage renal disease. The range of symptoms observed in PKD is due to mutations in cilia-localising genes, resulting in changes in cellular signalling. As such, compounds that are currently in preclinical and clinical trials target some of these signalling pathways that are dysregulated in PKD. In this review, we highlight these pathways including cAMP, EGF and AMPK signalling and drugs that target them and may show promise in lessening the disease burden of PKD patients. At present, tolvaptan is the only approved therapy for ADPKD, however, it carries several adverse side effects whilst comparatively, no pharmacological drug is approved for ARPKD treatment. Aside from this, drugs that have been the subject of multiple clinical trials such as metformin, which targets AMPK signalling and somatostatins, which target cAMP signalling have shown great promise in reducing cyst formation and cellular proliferation. This review also discusses other potential and novel targets that can be used for future interventions, such as β-catenin and TAZ, where research has shown that a reduction in the overexpression of these signalling components results in amelioration of disease phenotype. Thus, it becomes apparent that well-designed preclinical investigations and future clinical trials into these pathways and other potential signalling targets are crucial in bettering disease prognosis for PKD patients and could lead to personalised therapy approaches.

scholarly journals Tubular STAT3 Limits Renal Inflammation in Autosomal Dominant Polycystic Kidney Disease

2020 ◽  
Vol 31 (5) ◽  
pp. 1035-1049 ◽  
Author(s):  
Amandine Viau ◽  
Maroua Baaziz ◽  
Amandine Aka ◽  
Manal Mazloum ◽  
Clément Nguyen ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Primary Cilia ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Polycystic Kidneys ◽  
Renal Inflammation ◽  
Tubular Cells ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

BackgroundThe inactivation of the ciliary proteins polycystin 1 or polycystin 2 leads to autosomal dominant polycystic kidney disease (ADPKD). Although signaling by primary cilia and interstitial inflammation both play a critical role in the disease, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, a component of the cilia proteome that is involved in crosstalk between immune and nonimmune cells in various tissues, has been suggested as a factor fueling ADPKD progression.MethodTo explore how STAT3 intersects with cilia signaling, renal inflammation, and cyst growth, we used conditional murine models involving postdevelopmental ablation of Pkd1, Stat3, and cilia, as well as cultures of cilia-deficient or STAT3-deficient tubular cell lines.ResultsOur findings indicate that, although primary cilia directly modulate STAT3 activation in vitro, the bulk of STAT3 activation in polycystic kidneys occurs through an indirect mechanism in which primary cilia trigger macrophage recruitment to the kidney, which in turn promotes Stat3 activation. Surprisingly, although inactivating Stat3 in Pkd1-deficient tubules slightly reduced cyst burden, it resulted in a massive infiltration of the cystic kidneys by macrophages and T cells, precluding any improvement of kidney function. We also found that Stat3 inactivation led to increased expression of the inflammatory chemokines CCL5 and CXCL10 in polycystic kidneys and cultured tubular cells.ConclusionsSTAT3 appears to repress the expression of proinflammatory cytokines and restrict immune cell infiltration in ADPKD. Our findings suggest that STAT3 is not a critical driver of cyst growth in ADPKD but rather plays a major role in the crosstalk between immune and tubular cells that shapes disease expression.

scholarly journals Sequential tubular cell and basement membrane changes in polycystic kidney disease.

1992 ◽  
Vol 3 (2) ◽  
pp. 244-253
Author(s):  
F A Carone ◽  
S Nakamura ◽  
P Punyarit ◽  
Y S Kanwar ◽  
W J Nelson
Keyword(s):  
Cell Proliferation ◽  
Kidney Disease ◽  
Basement Membrane ◽  
Polycystic Kidney Disease ◽  
Apical Cell ◽  
Renal Cysts ◽  
Polycystic Kidney ◽  
Apical Cell Membrane ◽  
Tubular Cells ◽  
Collecting Tubules

Tubular basement membrane (BM) changes (dysmorphogenesis), cell proliferation, and fluid accumulation related to the altered location of Na,K-ATPase are purported essential key events in the development and progression of renal cysts. These changes were assessed daily in Phenol II (2-amino-4-hydroxyphenyl-5-phenyl thiazole)-treated rats, which rapidly develop marked and progressive cystic change of all collecting tubules (CT). At Day 1, 12% of CT were cystic and their BM were thickened severalfold. At Day 4, 30% of CT were cystic and their BM remained thickened. BM of cystic tubules showed decreased staining for heparan sulfate proteoglycan and increased staining for fibronectin. Proliferation, as determined by (3H)thymidine, incorporation, was not significant until Day 2 and involved cystic and noncystic tubular cells as well as interstitial cells. As cystic changes progressed, cell proliferation decreased. By immunohistochemistry, the altered location of Na,K-ATPase in epithelial cells lining cysts was primarily detected after Day 2 and consisted of focal loss from basal and/or lateral cell membranes and localization in the cell cytoplasm. Only rarely was Na,K-ATPase localized to the apical cell membrane. After the removal of Phenol II, cystic tubular cells, BM, and Na,K-ATPase returned to normal. Thus, in this model of polycystic kidney disease, initial cyst formation occurred in tandem with BM structural change whereas cell proliferation and altered location of Na,K-ATPase occurred after the appearance of cysts.

scholarly journals Tubular STAT3 limits renal inflammation in autosomal dominant polycystic kidney disease

2019 ◽  
Author(s):  
Amandine Viau ◽  
Maroua Baziz ◽  
Amandine Aka ◽  
Clément Nguyen ◽  
E. Wolfgang Kuehn ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Primary Cilia ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Polycystic Kidneys ◽  
Renal Inflammation ◽  
Tubular Cells ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cyst Growth

ABSTRACTThe inactivation of the ciliary proteins polycystin 1 or 2 leads to autosomal dominant polycystic kidney disease (ADPKD), the leading genetic cause of chronic kidney disease. Both cilia signaling and interstitial inflammation play a critical role in the disease. Yet, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, which is suspected to fuel ADPKD progression, is involved in crosstalks between immune and non-immune cells in various tissues and is a component of the cilia proteome. Here, we explore how STAT3 intersects with cilia signaling, renal inflammation and cyst growth using conditional murine models of post-developmental Pkd1, Stat3 and cilia ablation. Our results indicate that, although primary cilia directly modulate STAT3 activation in vitro, the bulk of STAT3 activation in polycystic kidneys occurs through an indirect mechanism in which primary cilia trigger macrophage recruitment to the kidney, which in turn promotes STAT3 activation. Surprisingly, while disrupting Stat3 in Pkd1 deficient tubules slightly reduced cyst burden, it resulted in a massive infiltration of the cystic kidneys by macrophages and T cells, precluding any improvement of kidney function. Mechanistically, STAT3 represses the expression of the inflammatory chemokines CCL5 and CXCL10 in polycystic kidneys and cultured tubular cells. These results demonstrate that STAT3 is not a critical driver of cyst growth in ADPKD but plays a major role in the crosstalk between immune and tubular cells that shapes disease expression.

Autosomal Dominant Polycystic Kidney Disease in Persian and Persian-cross Cats

1997 ◽  
Vol 34 (2) ◽  
pp. 117-126 ◽  
Author(s):  
K. A. Eaton ◽  
D. S. Biller ◽  
S. P. DiBartola ◽  
M. J. Radin ◽  
M. L. Wellman
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Lectin Staining ◽  
Renal Tubular Epithelium ◽  
Cardiac Lesions ◽  
Autosomal Dominant Polycystic Kidney ◽  
Renal Tubular ◽  
Cyst Lining

A form of autosomal dominant polycystic kidney disease (ADPKD) similar in clinical features to human ADPKD occurs in the Persian cat. We characterized the morphologic and immunohistochemical features of this disease in a colony of affected cats. Complete postmortem examinations were performed on 11 normal and 22 affected cats ranging in age from 3 months to 10 years. Kidneys were evaluated by gross and histologic examination, ultrastructure, lectin staining, bromodeoxyuridine immunochemistry for labeling index, and immunochemistry for distribution of Na/K ATPase. Feline ADPKD was characterized by variable numbers of cysts in the renal cortex and medulla. Ultrastructural examination and lectin staining suggested that cysts arose from proximal and distal nephron segments. Bromodeoxyuridine labeling demonstrated increased proliferation of epithelium lining some cysts in young cats. Immunohistochemical staining showed variable translocation of Na/K ATPase from the basolateral membranes of cyst-lining cells to the cytoplasm or luminal membranes. Cystic renal disease commonly was associated with chronic tubulointerstitial nephritis and hepatobiliary hyperplasia and fibrosis. Focal hyperplasia of renal tubular epithelium, hepatic cysts, and cardiac lesions were present in some cats. Feline ADPKD shares many morphologic and pathogenetic features with human ADPKD.

scholarly journals Novel Therapeutic Strategies Targeting Molecular Pathways of Cystogenesis in Autosomal Polycystic Kidney Disease

2017 ◽  
Vol 1 (1) ◽  
pp. 35-49 ◽  
Author(s):  
Maurizio Salvadori ◽  
Aris Tsalouchos
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Molecular Pathways ◽  
Polycystic Kidney ◽  
Cellular Targets ◽  
Progressive Development ◽  
Autosomal Dominant Polycystic Kidney ◽  
Renal Tubular ◽  
Novel Therapeutic Strategies ◽  
Inherited Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease that results from mutations in PKD1 or PKD2. The disease is characterized by the progressive development of fluid-filled cysts derived from renal tubular epithelial cells that destroy the architecture of the renal parenchyma and lead to kidney failure. Until recently, the causes and the molecular pathways that lead to cystogenesis remained obscure. In the last decade, enormous progress has been made in understanding the pathogenesis of ADPKD and the development of new therapies. The purpose of this review is to update on the promising therapies that are being developed and tested based on knowledge of recent advances in molecular and cellular targets involved in cystogenesis.

An endocytosis defect as a possible cause of proteinuria in polycystic kidney disease

2001 ◽  
Vol 280 (2) ◽  
pp. F244-F253 ◽  
Author(s):  
Nicholas Obermüller ◽  
Bettina Kränzlin ◽  
Werner F. Blum ◽  
Norbert Gretz ◽  
Ralph Witzgall
Keyword(s):  
Growth Factor ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Polycystic Kidney ◽  
Endocytic Machinery ◽  
Proximal Tubular ◽  
Autosomal Dominant Polycystic Kidney ◽  
Renal Tubular ◽  
Cyst Lining

Because proteinuria has been demonstrated in patients with autosomal-dominant polycystic kidney disease (ADPKD), we have investigated whether proteinuria also occurs in the ( cy/ +) rat, a widely used model for ADPKD. Increased urinary excretion of proteins, in particular of albumin, can be found in 16-wk-old ( cy/ +) rats, with a gel electrophoresis pattern compatible with a tubular origin of proteinuria. Using FITC-labeled dextran as an in vivo tracer for renal tubular endosomal function, we could show that portions of cyst-lining epithelia from proximal tubules have lost the ability to endocytose, which is necessary for the reabsorption of low-molecular-weight proteins. By immunohistochemistry, the expression of other proteins implicated in endocytosis, such as the chloride channel ClC-5 and the albumin receptor megalin, correlated well with the presence and absence of FITC-dextran in cysts. As an example of growth factor systems possibly being affected by this endocytosis defect, we could detect increased urinary levels of insulin-like growth factor-I protein in ( cy/ +) animals. These data indicate that proteinuria and albuminuria in the aforementioned rat model for ADPKD are due to a loss of the endocytic machinery in epithelia of proximal tubular cysts. This may also affect the concentration of different growth factors and hormones in cyst fluids and thus modulate cyst development.

scholarly journals Macrophage migration inhibitory factor is regulated by HIF-1α and cAMP and promotes renal cyst cell proliferation in a macrophage-independent manner

2020 ◽  
Vol 98 (11) ◽  
pp. 1547-1559
Author(s):  
Wajima Safi ◽  
Andre Kraus ◽  
Steffen Grampp ◽  
Johannes Schödel ◽  
Bjoern Buchholz
Keyword(s):  
Cell Proliferation ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Macrophage Migration Inhibitory Factor ◽  
Macrophage Migration ◽  
Polycystic Kidney ◽  
Tubular Cells ◽  
Cyst Lining ◽  
Cyst Growth

Abstract Progressive cyst growth leads to decline of renal function in polycystic kidney disease. Macrophage migration inhibitory factor (MIF) was found to be upregulated in cyst-lining cells in a mouse model of polycystic kidney disease and to promote cyst growth. In addition, MIF can be secreted by tubular cells and may contribute to cyst growth in an autocrine manner. However, the underlying mechanisms leading to induction of MIF in cyst-lining cells remained elusive. Here, we demonstrate that hypoxia-inducible transcription factor (HIF) 1α upregulates MIF in cyst-lining cells in a tubule-specific PKD1 knockout mouse. Pharmacological stabilization of HIF-1α resulted in significant increase of MIF in cyst epithelial cells whereas tubule-specific knockout of HIF-1α prevented MIF upregulation. Identical regulation could be found for ABCA1, which has been shown to act as a transport protein for MIF. Furthermore, we show that MIF and ABCA1 are direct target genes of HIF-1α in human primary tubular cells. Next to HIF-1α and hypoxia, we found MIF being additionally regulated by cAMP which is a strong promotor of cyst growth. In line with these findings, HIF-1α- and cAMP-dependent in vitro cyst growth could be decreased by the MIF-inhibitor ISO-1 which resulted in reduced cyst cell proliferation. In conclusion, HIF-1α and cAMP regulate MIF in primary tubular cells and cyst-lining epithelial cells, and MIF promotes cyst growth in the absence of macrophages. In line with these findings, the MIF inhibitor ISO-1 attenuates HIF-1α- and cAMP-dependent in vitro cyst enlargement. Key messages • MIF is upregulated in cyst-lining cells in a polycystic kidney disease mouse model. • MIF upregulation is mediated by hypoxia-inducible transcription factor (HIF) 1α. • ABCA1, transport protein for MIF, is also regulated by HIF-1α in vitro and in vivo. • MIF is additionally regulated by cAMP, a strong promotor of cyst growth. • MIF-inhibitor ISO-1 reduces HIF-1α- and cAMP-dependent cyst growth.

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