- Semaphorin 7A in circulating regulatory T cells is increased in autosomal-dominant polycystic kidney disease and decreases with tolvaptan treatment. [Journal Article]
- CEClin Exp Nephrol 2018 Feb 16
- CONCLUSIONS: SEMA7A shows potential as both a therapeutic target in mammalian kidney fibrosis and as a marker of inflammation in ADPKD patients. SEMA7A expression was lower after tolvaptan treatment, which may reflect drug efficacy.
- Genotypic and phenotypic characterization of the Sdccag8Tn(sb-Tyr)2161B.CA1C2Ove mouse model. [Journal Article]
- PlosPLoS One 2018; 13(2):e0192755
- Nephronophthisis-related ciliopathies (NPHP-RC) are a group of disorders that present with end-stage renal failure in childhood/adolescence, kidney cysts, retinal degeneration, and cerebellar hypopla...
Nephronophthisis-related ciliopathies (NPHP-RC) are a group of disorders that present with end-stage renal failure in childhood/adolescence, kidney cysts, retinal degeneration, and cerebellar hypoplasia. One disorder that shares clinical features with NPHP-RC is Bardet-Biedl Syndrome (BBS). Serologically defined colon cancer antigen 8 (SDCCAG8; also known as NPHP10 and BBS16) is an NPHP gene that is also associated with BBS. To better understand the patho-mechanisms of NPHP and BBS caused by loss of SDCCAG8 function, we characterized an SDCCAG8 mouse model (Sdccag8Tn(sb-Tyr)2161B.CA1C2Ove) generated by Sleeping Beauty Transposon (SBT)-mediated insertion mutagenesis. Consistent with the previously reported, independent SDCCAG8 mouse models, our mutant mice display pre-axial polydactyly in their hind limbs. In addition, we report patterning defects in the secondary palate, brain abnormalities, as well as neonatal lethality associated with developmental defects in the lung in our mouse model. The neonatal lethality phenotype is genetic background dependent and rescued by introducing 129S6/SvEvTac background. Genetic modifier(s) responsible for this effect were mapped to a region between SNPs rs3714172 and rs3141832 on chromosome 11. While determining the precise genetic lesion in our mouse model, we found that SBT insertion resulted in a deletion of multiple exons from both Sdccag8 and its neighboring gene Akt3. We ascribe the patterning defects in the limb and the secondary palate as well as lung abnormalities to loss of SDCCAG8, while the developmental defects in the brain are likely due to the loss of AKT3. This mouse model may be useful to study features not observed in other SDCCAG8 models but cautions are needed in interpreting data.
- Polycystin-2 is an essential ion channel subunit in the primary cilium of the renal collecting duct epithelium. [Journal Article]
- EElife 2018 Feb 14; 7
- Mutations in the polycystin genes,PKD1orPKD2,results in Autosomal Dominant Polycystic Kidney Disease (ADPKD). Although a genetic basis of ADPKD is established, we lack a clear understanding of polycy...
Mutations in the polycystin genes,PKD1orPKD2,results in Autosomal Dominant Polycystic Kidney Disease (ADPKD). Although a genetic basis of ADPKD is established, we lack a clear understanding of polycystin proteins' functions as ion channels. This question remains unsolved largely because polycystins localize to the primary cilium - a tiny, antenna-like organelle. Using a new ADPKD mouse model, we observe primary cilia that are abnormally long in cells associated with cysts after conditional ablation ofPkd1orPkd2. Using primary cultures of collecting duct cells, we show that polycystin-2, but not polycystin-1, is a required subunit for the ion channel in the primary cilium. The polycystin-2 channel preferentially conducts K+and Na+; intraciliary Ca2+, enhances its open probability. We introduce a novel method for measuring heterologous polycystin-2 channels in cilia, which will have utility in characterizingPKD2variants that cause ADPKD.
- A novel UMOD gene mutation associated with chronic kidney failure at a young age. [Journal Article]
- CNClin Nephrol 2018 Feb 09
- Autosomal dominant tubulointerstitial kidney disease (ADTKD) belongs to a group of renal hereditary disorders linked by common findings of tubulointerstitial disease and dominant inheritance. The ren...
Autosomal dominant tubulointerstitial kidney disease (ADTKD) belongs to a group of renal hereditary disorders linked by common findings of tubulointerstitial disease and dominant inheritance. The renal clinical phenotype is characterized by chronic kidney disease, hyperuricemia, gout, and, inconstantly, renal cysts. Uromodulin (UMOD) gene mutations are related to the clinical phenotype of ADTKD-UMOD. We describe here a novel heterozygous mutation of UMOD (c.249C>G; p.Cys83Trp) in an affected 9-year-old boy with progressive renal impairment and hyperuricemia. His mother is also affected and received renal transplantation at the age of 31 years. We assume that this variant is likely to be the causative mutation in this family as it segregates with the disease, it is not present in the genomic databases, and it is predicted to be damaging by the principal software tools. Considering the progressive renal impairment of our proband at an early age (serum creatinine elevation at the age of 6, hyperuricemia at the age of 9) and the early age at end-stage renal disease of his mother, we hypothesize that this variant is associated with a severe clinical phenotype. .
- Ganetespib limits ciliation and cystogenesis in autosomal-dominant polycystic kidney disease (ADPKD). [Journal Article]
- FJFASEB J 2018 Jan 10; :fj201700909R
- Autosomal-dominant polycystic kidney disease (ADPKD) is associated with progressive formation of renal cysts, kidney enlargement, hypertension, and typically end-stage renal disease. In ADPKD, inheri...
Autosomal-dominant polycystic kidney disease (ADPKD) is associated with progressive formation of renal cysts, kidney enlargement, hypertension, and typically end-stage renal disease. In ADPKD, inherited mutations disrupt function of the polycystins (encoded by PKD1 and PKD2), thus causing loss of a cyst-repressive signal emanating from the renal cilium. Genetic studies have suggested ciliary maintenance is essential for ADPKD pathogenesis. Heat shock protein 90 (HSP90) clients include multiple proteins linked to ciliary maintenance. We determined that ganetespib, a clinical HSP90 inhibitor, inhibited proteasomal repression of NEK8 and the Aurora-A activator trichoplein, rapidly activating Aurora-A kinase and causing ciliary loss in vitro. Using conditional mouse models for ADPKD, we performed long-term (10 or 50 wk) dosing experiments that demonstrated HSP90 inhibition caused durable in vivo loss of cilia, controlled cystic growth, and ameliorated symptoms induced by loss of Pkd1 or Pkd2. Ganetespib efficacy was not increased by combination with 2-deoxy-d-glucose, a glycolysis inhibitor showing some promise for ADPKD. These studies identify a new biologic activity for HSP90 and support a cilia-based mechanism for cyst repression.-Nikonova, A. S., Deneka, A. Y., Kiseleva, A. A., Korobeynikov, V., Gaponova, A., Serebriiskii, I. G., Kopp, M. C., Hensley, H. H., Seeger-Nukpezah, T. N., Somlo, S., Proia, D. A., Golemis, E. A. Ganetespib limits ciliation and cystogenesis in autosomal-dominant polycystic kidney disease (ADPKD).
- Imaging Follow-up of Low-Risk Incidental Pancreas and Kidney Findings: Effects of Patient Age and Comorbidity on Projected Life Expectancy. [Journal Article]
- RRadiology 2018 Feb 05; :171701
- Purpose To determine the effects of patient age and comorbidity level on life expectancy (LE) benefits associated with imaging follow-up of Bosniak IIF renal cysts and pancreatic side-branch (SB) int...
Purpose To determine the effects of patient age and comorbidity level on life expectancy (LE) benefits associated with imaging follow-up of Bosniak IIF renal cysts and pancreatic side-branch (SB) intraductal papillary mucinous neoplasms (IPMNs). Materials and Methods A decision-analytic Markov model to evaluate LE benefits was developed. Hypothetical cohorts with varied age (60-80 years) and comorbidities (none, mild, moderate, or severe) were evaluated. For each finding, LE projections from two strategies were compared: imaging follow-up and no imaging follow-up. Under follow-up, it was assumed that cancers associated with the incidental finding were successfully treated before they spread. For patients without follow-up, mortality risks from Bosniak IIF cysts (renal cell carcinoma) and SBIPMNs (pancreatic ductal adenocarcinoma) were incorporated. Model assumptions and parameter uncertainty were evaluated in sensitivity analysis. Results In the youngest, healthiest cohorts (age, 60 years; no comorbidities), projected LE benefits from follow-up were as follows: Bosniak IIF cyst, 6.5 months (women) and 5.8 months (men); SBIPMN, 6.4 months (women) and 5.3 months (men). Follow-up of Bosniak IIF cysts in 60-year-old women with severe comorbidities yielded a LE benefit of 3.9 months; in 80-year-old women with no comorbidities, the benefit was 2.8 months, and with severe comorbidities the benefit was 1.5 months. Similar trends were observed in men and for SBIPMN. Results were sensitive to the performance of follow-up for cancer detection; malignancy risks; and stage at presentation of malignant, unfollowed Bosniak IIF cysts. Conclusion With progression of age and comorbidity level, follow-up of low-risk incidental findings yields increasingly limited benefits for patients.©RSNA, 2018 Online supplemental material is available for this article.
- The Inv compartment of renal cilia is an intraciliary signal activating center to phosphorylate ANKS6. [Journal Article]
- KIKidney Int 2018 Jan 30
- Connections between cilia and renal cystic diseases are well known, yet molecular mechanisms remain undefined. Cysto-proteins localized in the Inv compartment of cilia (INV, NPHP3, NEK8, and ANKS6) c...
Connections between cilia and renal cystic diseases are well known, yet molecular mechanisms remain undefined. Cysto-proteins localized in the Inv compartment of cilia (INV, NPHP3, NEK8, and ANKS6) constitute a distinct group. Here we created and analyzed mutant mice (G2A mice) with a defective cilia localization signal in the Nphp3 gene. Mutant NPHP3 was absent the binding capacity of UNC119, a carrier protein responsible for the delivery of myristoylated cargo to the cilium, so ciliary localization was reduced or lost in the kidney but not in the embryonic node. Mutant mice developed renal cysts but not situs abnormalities. Although ciliary localization of INV, NEK8, and ANKS6 did not change in the kidneys of Nphp3 mutant mice, ANKS6 phosphorylation was impaired. In general, ANKS6 levels decrease with age in the kidneys of wild-type mice. However, cystic kidneys in G2A and Inv mice maintained high levels of a non-phosphorylated form of ANKS6. We found INV and NPHP3 cooperate and promote ANKS6 phosphorylation by NEK8 in renal cilia. Thus, there is a novel signaling path from cilia in which ANKS6 functions as a signal mediator and link between cilia and the cytoplasm to regulate kidney morphogenesis.
- Renal cyst masses (Bosniak category II-III) may be over evaluated by the Bosniak criteria based on MR findings. [Journal Article]
- MMedicine (Baltimore) 2017; 96(51):e9361
- A classification system of renal cysts developed by Bosniak is based on computed tomography (CT) findings and has been applied to deal with the complex cystic renal masses. Magnetic resonance (MR) ha...
A classification system of renal cysts developed by Bosniak is based on computed tomography (CT) findings and has been applied to deal with the complex cystic renal masses. Magnetic resonance (MR) has excellent soft-tissue resolution, it has been used to further evaluate some complex renal lesions, especially those suspected of containing soft tissue components and hyperattenuating cystic lesions seen on CT. Compared with CT, MR images may find additional information, which may lead to inconsistent classification. However, at present, there is no consensus on the treatment of these inconsistent lesions. This study aimed to investigate the value of MR in the evaluation of renal cystic masses by using the Bosniak classification system and improve understanding of the MR features of renal cyst masses.The present study retrospectively analyzed 35 renal cyst masses in 34 patients (10 men and 24 women with age from 20 to 65 years old, with an average of 49 ± 12.08), who underwent both MR and computed tomography (CT) examinations within 6 months (range from 1 to 135 days with an average of 11 ± 24.16 days). Twenty-four lesions (9 category III and 15 category IV on CT) received surgical treatment, 4 category IIF lesions on CT were upgraded to category III on MR, which were finally accepted operative resection. The remaining 7 lesions (category II-IIF on both CT and MR) were followed up for at least 3 years. For each lesion, size of both cyst and solid component, presence of calcification, number of septa, thickness of wall and septa, and appearance of enhancement were analyzed. Each lesion was categorized by using Bosniak criteria on CT and MR, respectively. The MR findings were compared with CT and pathology or follow-up results.On MR, categories of the lesions were as follows: category IIF (n = 7), III (n = 12), IV (n = 16). On CT, categories of the lesions were as follows: II (n = 3), IIF (n = 8), III (n = 9), and IV (n = 15). Findings on MR and CT images were inconsistent in 8 (23%) lesions. Among them, 3 category II lesions on CT were classified as category IIF on MR images, 4 category IIF lesions on CT were upgraded to category III on MR, and 1 category III lesions to category IV. In these lesions, MR detected more increased wall/septa thickness (n = 8) and septa number (n = 3) than CT, resulting in an upgrade in classification. Based on the pathological results, 5 of category III (5/9, 56%) and all category IV (15/15, 100%) lesions on CT images were malignant. On MR, 4 of category III (4/12, 33%) and all category IV (16/16, 100%) lesions were malignant.The renal cyst masses in some cases, especially category II to III lesions, may be over evaluated by the Bosniak criteria based on MR findings. It is necessary to combine MR features with CT findings in evaluation and management of these cases with renal cystic masses.
- Wnt Signaling in Kidney Development and Disease. [Journal Article]
- PMProg Mol Biol Transl Sci 2018; 153:181-207
- Wnt signal cascade is an evolutionarily conserved, developmental pathway that regulates embryogenesis, injury repair, and pathogenesis of human diseases. It is well established that Wnt ligands trans...
Wnt signal cascade is an evolutionarily conserved, developmental pathway that regulates embryogenesis, injury repair, and pathogenesis of human diseases. It is well established that Wnt ligands transmit their signal via canonical, β-catenin-dependent and noncanonical, β-catenin-independent mechanisms. Mounting evidence has revealed that Wnt signaling plays a key role in controlling early nephrogenesis and is implicated in the development of various kidney disorders. Dysregulations of Wnt expression cause a variety of developmental abnormalities and human diseases, such as congenital anomalies of the kidney and urinary tract, cystic kidney, and renal carcinoma. Multiple Wnt ligands, their receptors, and transcriptional targets are upregulated during nephron formation, which is crucial for mediating the reciprocal interaction between primordial tissues of ureteric bud and metanephric mesenchyme. Renal cysts are also associated with disrupted Wnt signaling. In addition, Wnt components are important players in renal tumorigenesis. Activation of Wnt/β-catenin is instrumental for tubular repair and regeneration after acute kidney injury. However, sustained activation of this signal cascade is linked to chronic kidney diseases and renal fibrosis in patients and experimental animal models. Mechanistically, Wnt signaling controls a diverse array of biologic processes, such as cell cycle progression, cell polarity and migration, cilia biology, and activation of renin-angiotensin system. In this chapter, we have reviewed recent findings that implicate Wnt signaling in kidney development and diseases. Targeting this signaling may hold promise for future treatment of kidney disorders in patients.
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- A case of unilateral nephrectomy performed for autosomal dominant polycystic kidney disease with marked unilateral enlargement. [Journal Article]
- CCCEN Case Rep 2018 Jan 31
- Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the occurrence of multiple cysts that increase the size of both kidneys, progressively reducing kidney function. Usually the c...
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the occurrence of multiple cysts that increase the size of both kidneys, progressively reducing kidney function. Usually the cysts occur bilaterally, and there is no difference in the degree of cyst enlargement between the left and right. Here, we report a case of ADPKD in which kidney size increased markedly on the left side and was accompanied by severe abdominal distension and discomfort. Renal dynamic scintigraphy revealed a severe reduction in function of the left kidney compared with the right. Open left nephrectomy was performed. No change in renal function was observed postoperatively [preoperative estimated glomerular filtration rate (eGFR): 57.6 mL/min/1.73 m2, 3-month postoperative eGFR: 56.4 mL/min/1.73 m2], and the abdominal symptoms subsided. When one kidney is markedly larger than the other, the cause and status of the laterality should be evaluated by using renal dynamic scintigraphy in addition to other examinations such as computed tomography or magnetic resonance imaging. Unilateral nephrectomy should be considered as a potential treatment.