Macrophages Promote Cyst Growth in Polycystic Kidney Disease

Karihaloo, Anil; Koraishy, Farrukh M.; Huen, Sarah C.; Lee, Yashang; Merrick, David; Caplan, Michael J.; Somlo, Stefan; Cantley, Lloyd G.

doi:10.1681/asn.2011010084

Cited by 201 publications

(223 citation statements)

References 23 publications

(29 reference statements)

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“…Although not analyzed here, these interstitial cells are likely fibroblasts, macrophages, and other inflammatory components. 18 A Proliferative Proximal Tubule Environment Is Insufficient for Rapid Cyst Formation Our findings are consistent with a potential causative role of proliferation in the cystic phenotype. However, a caveat of IR is that it causes additional effects other than proliferation, including loss of epithelial characteristics and dedifferentiation, cell necrosis and apoptosis, and inflammation.…”

Section: Temporal Proliferation Analyses In the Kidneysupporting

confidence: 82%

“…10 Alternatively, inflammation is associated with renal injury and recent studies have demonstrated that depletion of infiltrating macrophages has protective effects on cyst severity and renal function. 18 The goal of this study was to more specifically test the role of proliferation as a facilitator of rapid cyst formation using an approach that limited confounding factors. We utilized adultinduced Ift88 mutants carrying the Cux1…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, macrophages infiltrate the kidney in response to inflammatory cytokines expressed by tubule epithelium in Polycystin-1 mutants and chemical-mediated ablation of these macrophages reduced cyst severity and improved renal function. 18 In addition, if one evaluates the effect of antiproliferative therapies on cystogenesis with the immune system in mind, the effects may not be on the renal epithelium but rather the infiltrating immune cells. These combined observations suggest that perhaps polycystic kidney disease is a disease of altered inflammatory process/aberrant wound repair.…”

Section: Discussionmentioning

confidence: 99%

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Proximal Tubule Proliferation Is Insufficient to Induce Rapid Cyst Formation after Cilia Disruption

Sharma

Malarkey

Berbari

et al. 2013

Journal of the American Society of Nephrology

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Disrupting the function of cilia in mouse kidneys results in rapid or slow progression of cystic disease depending on whether the animals are juveniles or adults, respectively. Renal injury can also markedly accelerate the renal cyst formation that occurs after disruption of cilia in adult mice. Rates of cell proliferation are markedly higher in juvenile than adult kidneys and increase after renal injury, suggesting that cell proliferation may enhance the development of cysts. Here, we induced cilia loss in the kidneys of adult mice in the presence or absence of a Cux-1 transgene, which maintains cell proliferation. By using this model, we were able to avoid additional factors such as inflammation and dedifferentiation, which associate with renal injury and may also influence the rate of cystogenesis. After induction of cilia loss, cystic disease was not more pronounced in adult mice with the Cux-1 transgene compared with those without the transgene. In conclusion, these data suggest that proliferation is unlikely to be the sole mechanism underlying the rapid cystogenesis observed after injury in mice that lose cilia function in adulthood.

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Section: Temporal Proliferation Analyses In the Kidneysupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Proximal Tubule Proliferation Is Insufficient to Induce Rapid Cyst Formation after Cilia Disruption

Sharma

Malarkey

Berbari

et al. 2013

Journal of the American Society of Nephrology

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“…We noticed a very prominent infiltration rate in the cystic tissues for all of these three markers, in line with previous studies. 19 Of interest, 2DG significantly reduced the levels of CD45-expressing cells as assayed both by RT-PCR and immunohistochemistry ( Figure 4, C and D). The reduced infiltration rates might reflect a reduced tissue damage in the long-term PKD model.…”

Section: Dg Improves the Cystic Index And Inflammatorymentioning

confidence: 86%

2-Deoxy-d-Glucose Ameliorates PKD Progression

Chiaravalli¹,

Rowe²,

Mannella³

et al. 2015

JASN

154

120

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Autosomal dominant polycystic kidney disease (ADPKD) is an important cause of ESRD for which there exists no approved therapy in the United States. Defective glucose metabolism has been identified as a feature of ADPKD, and inhibition of glycolysis using glucose analogs ameliorates aggressive PKD in preclinical models. Here, we investigated the effects of chronic treatment with low doses of the glucose analog 2-deoxy-D-glucose (2DG) on ADPKD progression in orthologous and slowly progressive murine models created by inducible inactivation of the Pkd1 gene postnatally. As previously reported, early inactivation (postnatal days 11 and 12) of Pkd1 resulted in PKD developing within weeks, whereas late inactivation (postnatal days 25-28) resulted in PKD developing in months. Irrespective of the timing of Pkd1 gene inactivation, cystic kidneys showed enhanced uptake of 13 C-glucose and conversion to 13 C-lactate. Administration of 2DG restored normal renal levels of the phosphorylated forms of AMPactivated protein kinase and its target acetyl-CoA carboxylase. Furthermore, 2DG greatly retarded disease progression in both model systems, reducing the increase in total kidney volume and cystic index and markedly reducing CD45-positive cell infiltration. Notably, chronic administration of low doses (100 mg/kg 5 days per week) of 2DG did not result in any obvious sign of toxicity as assessed by analysis of brain and heart histology as well as behavioral tests. Our data provide proof of principle support for the use of 2DG as a therapeutic strategy in ADPKD.

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“…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%

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

Torres

Harris

2014

Journal of the American Society of Nephrology

243

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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Macrophages Promote Cyst Growth in Polycystic Kidney Disease

Cited by 201 publications

References 23 publications

Proximal Tubule Proliferation Is Insufficient to Induce Rapid Cyst Formation after Cilia Disruption

Proximal Tubule Proliferation Is Insufficient to Induce Rapid Cyst Formation after Cilia Disruption

2-Deoxy-d-Glucose Ameliorates PKD Progression

Strategies Targeting cAMP Signaling in the Treatment of Polycystic Kidney Disease

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