Glucose promotes secretion-dependent renal cyst growth

Kraus, Andre; Schley, Gunnar; Kunzelmann, Karl; Schreiber, Rainer; Peters, Dorien J.M.; Stadler, Ruth; Eckardt, Kai‐Uwe; Buchholz, Björn

doi:10.1007/s00109-015-1337-4

Cited by 18 publications

(7 citation statements)

References 39 publications

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“…analog that cannot be metabolized, reduces cell proliferation in human PKD cells and kidney cystogenesis in various murine models (5,6,9). Consistent with these results, higher glucose concentration increases kidney cyst growth (10), and hyperglycemia promotes cystogenesis, as well as kidney structural and functional damage in a nonorthologous rodent model of PKD (11).…”

Section: Adpkd a Disease Of Dysregulated Metabolism As Established By In Vitro And Animal Modelssupporting

confidence: 63%

Metabolic Reprogramming in Autosomal Dominant Polycystic Kidney Disease

Nowak

Hopp

2020

CJASN

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Autosomal dominant polycystic kidney disease is characterized by progressive development and enlargement of kidney cysts, leading to ESKD. Because the kidneys are under high metabolic demand, it is not surprising that mounting evidence suggests that a metabolic defect exists in in vitro and animal models of autosomal dominant polycystic kidney disease, which likely contributes to cystic epithelial proliferation and subsequent cyst growth. Alterations include defective glucose metabolism (reprogramming to favor aerobic glycolysis), dysregulated lipid and amino acid metabolism, impaired autophagy, and mitochondrial dysfunction. Limited evidence supports that cellular kidney metabolism is also dysregulated in humans with autosomal dominant polycystic kidney disease. There are notable overlapping features and pathways among metabolism, obesity, and/or autosomal dominant polycystic kidney disease. Both dietary and pharmacologic-based strategies targeting metabolic abnormalities are being considered as therapies to slow autosomal dominant polycystic kidney disease progression and are attractive, particularly given the slowly progressive nature of the disease. Dietary strategies include daily caloric restriction, intermittent fasting, time-restricted feeding, a ketogenic diet, and 2-deoxy-glucose as well as alterations to nutrient availability. Pharmacologic-based strategies include AMP-activated kinase activators, sodium glucose cotransporter-2 inhibitors, niacinamide, and thiazolidenediones. The results from initial clinical trials targeting metabolism are upcoming and anxiously awaited within the scientific and polycystic kidney disease communities. There continues to be a need for additional mechanistic studies to better understand the role of dysregulated metabolism in autosomal dominant polycystic kidney disease and for subsequent translation to clinical trials. Beyond single-intervention trials focused on metabolic reprograming in autosomal dominant polycystic kidney disease, great potential also exists by combining metabolic-focused therapeutic approaches with compounds targeting other signaling cascades altered in autosomal dominant polycystic kidney disease, such as tolvaptan.

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Section: Adpkd a Disease Of Dysregulated Metabolism As Established By In Vitro And Animal Modelssupporting

confidence: 63%

Metabolic Reprogramming in Autosomal Dominant Polycystic Kidney Disease

Nowak

Hopp

2020

CJASN

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“…CFTR expression was neither directly nor indirectly upregulated by HIF-1α [5,12]. Apart from the impact of oxygen supply, we have also shown recently that glucose concentration affects in vitro cyst growth and transcriptional regulation of ANO1 and P2Y2R, thereby promoting calcium-dependent chloride secretion [34]. Whether glucose-dependent upregulation of P2Y2R is mediated in a HIF-dependent or -independent way deserves further investigation.…”

Section: Discussionmentioning

confidence: 79%

P2Y2R is a direct target of HIF-1α and mediates secretion-dependent cyst growth of renal cyst-forming epithelial cells

Kraus

Grampp

Goppelt‐Struebe

et al. 2016

Purinergic Signalling

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Polycystic kidney diseases are characterized by numerous renal cysts that continuously enlarge resulting in compression of intact nephrons and tissue hypoxia. Recently, we have shown that hypoxia-inducible factor (HIF)-1α promotes secretion-dependent cyst expansion, presumably by transcriptional regulation of proteins that are involved in calciumactivated chloride secretion. Here, we report that HIF-1α directly activates expression of the purinergic receptor P2Y2R in human primary renal tubular cells. In addition, we found that P2Y2R is highly expressed in cyst-lining cells of human ADPKD kidneys as well as PKD1 orthologous mouse kidneys. Knockdown of P2Y2R in renal collecting duct cells inhibited calcium-dependent chloride secretion in Ussing chamber analyses. In line with these findings, knockdown of P2Y2R retarded cyst expansion in vitro and prevented ATPand HIF-1α-dependent cyst growth. In conclusion, P2Y2R mediates ATP-dependent cyst growth and is transcriptionally regulated by HIF-1α. These findings provide further mechanistic evidence on how hypoxia promotes cyst growth.

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“…Polycystic kidney disease cells displayed a proproliferative glycolytic phenotype with increased lactate formation and extracellular acidification [47]. High glucose concentrations may promote cyst growth through calcium-activated chloride secretion [48], whereas glycolytic inhibitors, such as 2-deoxyglucose (2DG), have protective effects against cyst progression [49]. Trehalose ingestion may also inhibit the absorption of glucose in the gut and exert some anti-glycolysis effects [19].…”

Section: Discussionmentioning

confidence: 99%

Effect of Trehalose Supplementation on Autophagy and Cystogenesis in a Mouse Model of Polycystic Kidney Disease

et al. 2018

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Autophagy impairment has been demonstrated in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) and could be a new target of treatment. Trehalose is a natural, nonreducing disaccharide that has been shown to enhance autophagy. Therefore, we investigated whether trehalose treatment reduces renal cyst formation in a Pkd1-hypomorphic mouse model. Pkd1 miRNA transgenic (Pkd1 miR Tg) mice and wild-type littermates were given drinking water supplemented with 2% trehalose from postnatal day 35 to postnatal day 91. The control groups received pure water or 2% sucrose for the control of hyperosmolarity. The effect on kidney weights, cystic indices, renal function, cell proliferation, and autophagic activities was determined. We found that Pkd1 miR Tg mice had a significantly lower renal mRNA expression of autophagy-related genes, including atg5, atg12, ulk1, beclin1, and p62, compared with wild-type control mice. Furthermore, immunohistochemical analysis showed that cystic lining cells had strong positive staining for the p62 protein, indicating impaired degradation of the protein by the autophagy-lysosome pathway. However, trehalose treatment did not improve reduced autophagy activities, nor did it reduce relative kidney weights, plasma blood urea nitrogen levels, or cystatin C levels in Pkd1 miR Tg mice. Histomorphological analysis revealed no significant differences in the renal cyst index, fibrosis score, or proliferative score among trehalose-, sucrose-, and water-treated groups. Our results demonstrate that adding trehalose to drinking water does not modulate autophagy activities and renal cystogenesis in Pkd1-deficient mice, suggesting that an oral supplement of trehalose may not affect the progression of ADPKD.

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Glucose promotes secretion-dependent renal cyst growth

Cited by 18 publications

References 39 publications

Metabolic Reprogramming in Autosomal Dominant Polycystic Kidney Disease

Metabolic Reprogramming in Autosomal Dominant Polycystic Kidney Disease

P2Y2R is a direct target of HIF-1α and mediates secretion-dependent cyst growth of renal cyst-forming epithelial cells

Effect of Trehalose Supplementation on Autophagy and Cystogenesis in a Mouse Model of Polycystic Kidney Disease

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