Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease

Torres, Jacob A.; Rezaei, Mina; Broderick, Caroline; Lin, Louis M.; Wang, Xiaofang; Höppe, Bernd; Cowley, Benjamin D.; Savica, Vincenzo; Torres, Vicente E.; Khan, Saeed R.; Holmes, Ross P.; Mrug, Michal; Weimbs, Thomas

doi:10.1172/jci128503

Cited by 66 publications

(70 citation statements)

References 80 publications

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“…To identify p-Stat3 signaling, we used a modified version of recently described protocol (29). Paraffin-embedded sections were rehydrated using a xylene and decreasing ethanol series, washed in Tris-buffered saline (TBS), and boiled in 10 mM sodium citrate buffer (pH 6) for 5 minutes in a 100°C water bath.…”

Section: Immunofluorescence Microscopymentioning

confidence: 99%

Interferon Regulatory Factor‐5 in Resident Macrophage Promotes Polycystic Kidney Disease

et al. 2020

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Background Autosomal dominant polycystic kidney disease is caused by genetic mutations in PKD1 or PKD2. Macrophages and their associated inflammatory cytokines promote cyst progression; however, transcription factors within macrophages that control cytokine production and cystic disease are unknown.Methods In these studies, we used conditional Pkd1 mice to test the hypothesis that macrophage-localized interferon regulatory factor-5 (IRF5), a transcription factor associated with production of cyst-promoting cytokines (TNFa, IL-6), is required for accelerated cyst progression in a unilateral nephrectomy (1K) model. Analyses of quantitative real-time PCR (qRT-PCR) and flow-cytometry data 3 weeks post nephrectomy, a time point before the onset of severe cystogenesis, indicate an accumulation of inflammatory infiltrating and resident macrophages in 1K Pkd1 mice compared with controls. qRT-PCR data from FACS cells at this time demonstrate that macrophages from 1K Pkd1 mice have increased expression of Irf5 compared with controls. To determine the importance of macrophage-localized Irf5 in cyst progression, we injected scrambled or IRF5 antisense oligonucleotide (ASO) in 1K Pkd1 mice and analyzed the effect on macrophage numbers, cytokine production, and renal cystogenesis 6 weeks post nephrectomy.Results Analyses of qRT-PCR and IRF5 ASO treatment significantly reduced macrophage numbers, Irf5 expression in resident-but not infiltrating-macrophages, and the severity of cystic disease. In addition, IRF5 ASO treatment in 1K Pkd1 mice reduced Il6 expression in resident macrophages, which was correlated with reduced STAT3 phosphorylation and downstream p-STAT3 target gene expression.Conclusions These data suggest that Irf5 promotes inflammatory cytokine production in resident macrophages resulting in accelerated cystogenesis.

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Section: Immunofluorescence Microscopymentioning

confidence: 99%

Interferon Regulatory Factor‐5 in Resident Macrophage Promotes Polycystic Kidney Disease

et al. 2020

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“…Thus, loss‐of‐function mutation in SLC2A9 resulted in low serum uric acid levels and thus insufficient antioxidant activity. In addition, crystal deposition (precipitation and crystallization of uric acid in the kidney) triggers tubule dilation that may accelerate cystogenesis in ADPKD environment as it has been previously suggested . Although urate crystals in the urinary sediment were not detected, the presence of high urinary uric acid concentration, increased FE‐uric acid and elevated uric acid clearance with low urine pH, are proper conditions which could increase the risk of urine uric acid crystallization‐precipitation in the proband.…”

Section: Discussionmentioning

confidence: 83%

“…Unfortunately, a percutaneous cyst aspiration and analysis of the cyst contents was not performed . Altogether, we hypothesized that tubular renal and cystic crystal deposition of uric acid in these conditions could accelerate ADPKD progression . For a better comprehension, see Figure .…”

Section: Discussionmentioning

confidence: 98%

“…However, ischemic or toxic damage are rare events in humans. Tubular crystal deposition leading to tubule dilation may constitute a “third hit” resulting in rapid cyst formation in polycystic kidney disease …”

Section: Discussionmentioning

confidence: 99%

“…RHUC is a heterogeneous genetic disorder characterized by impaired tubular transport, reabsorption insufficiency, and/or accelerated secretion of uric acid accompanied by severe complications, such as exercise induced AKI, CKD, and nephrolithiasis . Trying to unreveal disease actions of RHUC, the mechanism of exercise‐induced AKI in patients with RHUC has been dissected, and several mechanisms have been proposed based mainly in: the antioxidant activity of serum uric acid, the precipitation and crystallization of uric acid in the kidney, leading to nephrolithiasis and obstruction of renal tubules, and loss‐of‐function mutations in either SLC22A12 or SLC2A9 result not only in decreased uric acid absorption, but also in reduced secretion of organic anions to the tubular lumen.…”

Section: Discussionmentioning

confidence: 99%

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Coexistence of autosomal dominant polycystic kidney disease type 1 and hereditary renal hypouricemia type 2: A model of early‐onset and fast cyst progression

et al. 2020

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Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous inherited disease characterized by renal and extrarenal manifestations with progressive fluidfilled cyst development leading to end-stage renal disease. The rate of disease progression in ADPKD exhibits high inter-and intrafamilial variability suggesting involvement of modifier genes and/or environmental factors. Renal hypouricemia (RHUC) is an inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury and chronic kidney disease (CKD).However, the two disorders have distinct and well-delineated genetic, biochemical, and clinical findings. Only a few cases of coexistence of ADPKD and RHUC (type 1) in a single individual have been reported. We report a family with two members: an ADPKD 24-year-old female which presented bilateral renal cysts in utero and hypouricemia since age 5, and her mother with isolated hypouricemia. Next-generation sequencing identified two mutations in two genes PKD1 and SLC2A9 in this patient and one isolated SLC2A9 mutation in her mother, showing RHUC type 2, associated to CKD. The coexistence of these two disorders provides evidence of SLC2A9 variant could act as a modifier change, with synergistic actions, that could promote cystogenesis and rapid ADPKD progression. This is the first case of coexistence of PKD1 and SLC2A9 mutations treated with tolvaptan.

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Characterization of renal fibrosis in rats with chronic kidney disease by in vivo tomoelastography

Krehl,

Hahndorf,

Stolzenburg

et al. 2023

NMR in Biomedicine

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Chronic kidney disease (CKD) is characterized by structural changes, such as tubular atrophy, renal fibrosis, and glomerulosclerosis, all of which affect the viscoelastic properties of biological tissues. However, detection of renal viscoelasticity changes because diagnostic markers by in vivo elastography lack histopathological validation through animal models.Therefore, we investigated in vivo multiparametric magnetic resonance imaging (mp‐MRI), including multifrequency magnetic resonance elastography‐based tomoelastography, in the kidneys of 10 rats with adenine‐induced CKD and eight healthy controls. Kidney volume (in mm3), water diffusivity (apparent diffusion coefficient [ADC] in mm2/s), shear wave speed (SWS; in m/s; related to stiffness), and wave penetration rate (PR; in m/s; related to inverse viscosity) were quantified by mp‐MRI and correlated with histopathologically determined renal fibrosis (collagen area fraction [CAF]; in %). Kidney volume (40% ± 29%, p = 0.009), SWS (11% ± 12%, p = 0.016), and PR (20% ± 15%, p = 0.004) were significantly increased in CKD, which was accompanied by ADC (−24% ± 27%, p = 0.02). SWS, PR, and ADC were correlated with CAF with R = 0.63, 0.75, and −0.5 (all p < 0.05), respectively. In the CKD rats, histopathology showed tubule dilation due to adenine crystal deposition. Collectively, our results suggest that collagen accumulation during CKD progression transforms soft‐compliant renal tissue into a more rigid‐solid state with reduced water mobility. We hypothesized that tubule dilation—a specific feature of our model—might lead to higher intraluminal pressure, which could also contribute to elevated renal stiffness. Tomoelastography is a promising tool for noninvasively assessing disease progression, detecting biomechanical properties that are sensitive to different pathologic features of CKD.

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Crystal deposition triggers tubule dilation that accelerates cystogenesis in polycystic kidney disease

Cited by 66 publications

References 80 publications

Interferon Regulatory Factor‐5 in Resident Macrophage Promotes Polycystic Kidney Disease

Interferon Regulatory Factor‐5 in Resident Macrophage Promotes Polycystic Kidney Disease

Coexistence of autosomal dominant polycystic kidney disease type 1 and hereditary renal hypouricemia type 2: A model of early‐onset and fast cyst progression

Characterization of renal fibrosis in rats with chronic kidney disease by in vivo tomoelastography

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