Macrophages promote polycystic kidney disease progression

Swenson-Fields, Katherine I.; Vivian, Carolyn J.; Salah, Samia; Peda, Jacqueline D.; Davis, Bradley M; Rooijen, Nico van; Wallace, Darren P.; Fields, Timothy A.

doi:10.1038/ki.2012.446

Cited by 155 publications

(162 citation statements)

References 34 publications

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“…These observations have led to the hypothesis that alternatively activated M2 macrophages contribute to cell proliferation in PKD, as has been described in cancer and during the recovery from AKI. 116,117 After renal ischemia-reperfusion, macrophages infiltrate the kidney and undergo a phenotypic switch from classically activated proinflammatory M1 to alternatively activated M2 macrophages that promote tubular epithelial cell proliferation, tissue remodeling, and fibrogenesis. [118][119][120] STAT3 activation in PKD, as previously described in cancer, plays a critical role in the development and maintenance of an inflammatory microenvironment.…”

Section: Interstitial Inflammation and Fibrosismentioning

confidence: 99%

“…115 More recently, many alternatively activated macrophages aligned along cyst walls have been detected in polycystic kidneys from conditional Pkd1-knockout and Pkd2 WS25/2 mice. 116,117 Macrophage depletion by intraperitoneal liposomal clodronate administration inhibits epithelial cell proliferation and cyst growth and improves renal function. These observations have led to the hypothesis that alternatively activated M2 macrophages contribute to cell proliferation in PKD, as has been described in cancer and during the recovery from AKI.…”

Section: Interstitial Inflammation and Fibrosismentioning

confidence: 99%

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Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

Torres

Harris

2014

Journal of the American Society of Nephrology

244

218

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Polycystic kidney disease (PKD) is a leading cause of ESRD worldwide. In PKD, excessive cell proliferation and fluid secretion, pathogenic interactions of mutated epithelial cells with an abnormal extracellular matrix and alternatively activated interstitial macrophages, and the disruption of mechanisms controlling tubular diameter contribute to cyst formation. Studies with animal models suggest that several diverse pathophysiologic mechanisms, including dysregulation of intracellular calcium levels and cAMP signaling, mediate these cystogenic mechanisms. This article reviews the evidence implicating calcium and cAMP as central players in a network of signaling pathways underlying the pathogenesis of PKD and considers the therapeutic relevance of treatment strategies targeting cAMP signaling.

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Section: Interstitial Inflammation and Fibrosismentioning

confidence: 99%

Section: Interstitial Inflammation and Fibrosismentioning

confidence: 99%

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

Torres

Harris

2014

Journal of the American Society of Nephrology

244

218

View full text Add to dashboard Cite

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“…Next, we examined if these changes in the blood and lymphatic microvasculature might correlate with the inflammatory milieu in PKD by examining CD206/ Mrc1 + alternatively activated macrophages (M2), which have been functionally implicated in PKD cyst growth. 15,16 VEGFC significantly reduced these cells in Pkd1 nl/nl mice ( Figure 3, G-J). Treatment also led to significantly lower renal Mrc1 levels in Pkd1 nl/nl mice ( Figure 3K) although the reduction of another M2 marker, arginase 1 (Arg1), did not reach significance ( Figure 3L).…”

mentioning

confidence: 99%

Vascular Endothelial Growth Factor C for Polycystic Kidney Diseases

Huang¹,

Woolf

Kolatsi-Joannou³

et al. 2016

Journal of the American Society of Nephrology

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Polycystic kidney diseases (PKD) are genetic disorders characterized by progressive epithelial cyst growth leading to destruction of normally functioning renal tissue. Current therapies have focused on the cyst epithelium, and little is known about how the blood and lymphatic microvasculature modulates cystogenesis. Hypomorphic Pkd1 nl/nl mice were examined, showing that cystogenesis was associated with a disorganized pericystic network of vessels expressing platelet/endothelial cell adhesion molecule 1 and vascular endothelial growth factor receptor 3 (VEGFR3). The major ligand for VEGFR3 is VEGFC, and there were lower levels of Vegfc mRNA within the kidneys during the early stages of cystogenesis in 7-day-old Pkd1 nl/nl mice. Seven-day-old mice were treated with exogenous VEGFC for 2 weeks on the premise that this would remodel both the VEGFR3 + pericystic vascular network and larger renal lymphatics that may also affect the severity of PKD. Treatment with VEGFC enhanced VEGFR3 phosphorylation in the kidney, normalized the pattern of the pericystic network of vessels, and widened the large lymphatics in Pkd1 nl/nl mice.These effects were associated with significant reductions in cystic disease, BUN and serum creatinine levels. Furthermore, VEGFC administration reduced M2 macrophage pericystic infiltrate, which has been implicated in the progression of PKD. VEGFC administration also improved cystic disease in Cys1 cpk/cpk mice, a model of autosomal recessive PKD, leading to a modest but significant increase in lifespan. Overall, this study highlights VEGFC as a potential new treatment for some aspects of PKD, with the possibility for synergy with current epithelially targeted approaches.

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“…Advances in 3D tissue culture over the past 2 decades have improved the ability to model cyst development in vitro. However, previously published 3D tissue models of ADPKD have relied upon shortterm culture of Madin-Darby canine kidney (MDCK) cells (6)(7)(8)(9)(10)(11)(12) or cells from patients (13)(14)(15)(16)(17)(18) or PC1-null mice (19,20; for review, see ref. 21).…”

mentioning

confidence: 99%

Cyst formation following disruption of intracellular calcium signaling

Kuo¹,

DesRochers

Kimmerling

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in polycystin 1 and 2 (PC1 and PC2) cause the common genetic kidney disorder autosomal dominant polycystic kidney disease (ADPKD). It is unknown how these mutations result in renal cysts, but dysregulation of calcium (Ca 2+ ) signaling is a known consequence of PC2 mutations. PC2 functions as a Ca 2+ -activated Ca 2+ channel of the endoplasmic reticulum. We hypothesize that Ca 2+ signaling through PC2, or other intracellular Ca 2+ channels such as the inositol 1,4,5-trisphosphate receptor (InsP3R), is necessary to maintain renal epithelial cell function and that disruption of the Ca 2+ signaling leads to renal cyst development. The cell line LLC-PK1 has traditionally been used for studying PKD-causing mutations and Ca 2+ signaling in 2D culture systems. We demonstrate that this cell line can be used in long-term (8 wk) 3D tissue culture systems. In 2D systems, knockdown of InsP3R results in decreased Ca 2+ transient signals that are rescued by overexpression of PC2. In 3D systems, knockdown of either PC2 or InsP3R leads to cyst formation, but knockdown of InsP3R type 1 (InsP3R1) generated the largest cysts. InsP3R1 and InsP3R3 are differentially localized in both mouse and human kidney, suggesting that regional disruption of Ca 2+ signaling contributes to cystogenesis. All cysts had intact cilia 2 wk after starting 3D culture, but the cells with InsP3R1 knockdown lost cilia as the cysts grew. Studies combining 2D and 3D cell culture systems will assist in understanding how mutations in PC2 that confer altered Ca 2+ signaling lead to ADPKD cysts. primary cilia | polycysin 2 | calcium release T he commonly occurring genetic kidney disorder, autosomal dominant polycystic kidney disease (ADPKD), is the result of mutations in polycystin 1 or 2 (PC1 or PC2). The progressive cyst formation within all segments of the nephron that defines the disorder leads to renal failure requiring treatment by dialysis and/or organ transplantation (1-3). Altered Ca 2+ signaling is one of several pathways that have been implicated in the disease (4, 5). A major limitation toward elucidating the role of Ca 2+ signaling in cyst formation has been the lack of easily manipulated, physiologically relevant experimental methodologies.In the past, ADPKD research has relied largely upon data from mouse models and cells maintained in 2D cell culture. Mouse models have played a significant role in understanding the biology of cyst formation but are unable to fully recapitulate the physiology of disease progression in humans due to the inherent differences between the species including life span, genetics, and environment. Two-dimensional cell culture has the ability to provide information on signaling pathways and response to therapies in a fast, high-throughput manner, but is incapable of replicating the inherent 3D nature of cyst formation. Advances in 3D tissue culture over the past 2 decades have improved the ability to model cyst development in vitro. However, previously published 3D tissue models of ADPKD have relied upon shortter...

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Macrophages promote polycystic kidney disease progression

Cited by 155 publications

References 34 publications

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

Vascular Endothelial Growth Factor C for Polycystic Kidney Diseases

Cyst formation following disruption of intracellular calcium signaling

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