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Background Although studies have identified >55 genes as causing steroid-resistant nephrotic syndrome (SRNS) and localized its pathogenesis to glomerular podocytes, the disease mechanisms of SRNS remain largely enigmatic. We recently reported that individuals with mutations in COQ6, a coenzyme Q (also called CoQ 10 , CoQ, or ubiquinone) biosynthesis pathway enzyme, develop SRNS with sensorineural deafness, and demonstrated the beneficial effect of CoQ for maintenace of kidney function. Methods To study COQ6 function in podocytes, we generated a podocyte-specific Coq6 knockout mouse ( Coq6 podKO ) model and a transient siRNA-based COQ6 knockdown in a human podocyte cell line. Mice were monitored for development of proteinuria and assessed for development of glomerular sclerosis. Using a podocyte migration assay, we compared motility in COQ6 knockdown podocytes and control podocytes. We also randomly assigned 5-month-old Coq6 podKO mice and controls to receive no treatment or 2,4-dihydroxybenzoic acid (2,4-diHB), an analog of a CoQ precursor molecule that is classified as a food additive by health authorities in Europe and the United States. Results Abrogation of Coq6 in mouse podocytes caused FSGS and proteinuria (>46-fold increases in albuminuria). In vitro studies revealed an impaired podocyte migration rate in COQ6 knockdown human podocytes. Treating Coq6 podKO mice or cells with 2,4-diHB prevented renal dysfunction and reversed podocyte migration rate impairment. Survival of Coq6 podKO mice given 2,4diHB was comparable to that of control mice and significantly higher than that of untreated Coq6 podKO mice, half of which died by 10 months of age. Conclusions These findings reveal a potential novel treatment strategy for those cases of human nephrotic syndrome that are caused by a primary dysfunction in the CoQ 10 biosynthesis pathway.

Karyomegalic interstitial nephritis (KIN) is a chronic interstitial nephropathy characterized by tubulointerstitial nephritis and formation of enlarged nuclei in the kidneys and other tissues. We recently reported that recessive mutations in the gene encoding FANCD2/FANCI-associated nuclease 1 (FAN1) cause KIN in humans. FAN1 is a major component of the Fanconi anemia–related pathway of DNA damage response (DDR) signaling. To study the pathogenesis of KIN, we generated a Fan1 knockout mouse model, with abrogation of Fan1 expression confirmed by quantitative RT-PCR. Challenging Fan1−/− and wild-type mice with 20 mg/kg cisplatin caused AKI in both genotypes. In contrast, chronic injection of cisplatin at 2 mg/kg induced KIN that led to renal failure within 5 weeks in Fan1−/− mice but not in wild-type mice. Cell culture studies showed decreased survival and reduced colony formation of Fan1−/− mouse embryonic fibroblasts and bone marrow mesenchymal stem cells compared with wild-type counterparts in response to treatment with genotoxic agents, suggesting that FAN1 mutations cause chemosensitivity and bone marrow failure. Our data show that Fan1 is involved in the physiologic response of kidney tubular cells to DNA damage, which contributes to the pathogenesis of CKD. Moreover, Fan1−/− mice provide a new model with which to study the pathomechanisms of CKD.

The emotional health and wellbeing of children and adolescents and their families is of utmost importance. Pediatricians are at the front line in identifying mental illness in children and adolescents and either linking them to resources in the community or providing treatment options themselves. Collaboration and integrative health care models is the cornerstone of effective strategies to provide access and quality mental health care to children and families in communities across the country.

Recessive mutations in the SDCCAG8 gene cause a nephronophthisis-related ciliopathy with Bardet-Biedl syndrome-like features in humans. Our previous characterization of the orthologous Sdccag8gt/gt mouse model recapitulated the retinal-renal disease phenotypes and identified impaired DNA damage response signaling as an underlying disease mechanism in the kidney. However, several other phenotypic and mechanistic features of Sdccag8gt/gt mice remained unexplored. Here we show that Sdccag8gt/gt mice exhibit developmental and structural abnormalities of the skeleton and limbs, suggesting impaired Hedgehog (Hh) signaling. Indeed, cell culture studies demonstrate the requirement of SDCCAG8 for ciliogenesis and Hh signaling. Using an affinity proteomics approach, we demonstrate that SDCCAG8 interacts with proteins of the centriolar satellites (OFD1, AZI1), of the endosomal sorting complex (RABEP2, ERC1), and with non-muscle myosin motor proteins (MYH9, MYH10, MYH14) at the centrosome. Furthermore, we show that RABEP2 localization at the centrosome is regulated by SDCCAG8. siRNA mediated RABEP2 knockdown in hTERT-RPE1 cells leads to defective ciliogenesis, indicating a critical role for RABEP2 in this process. Together, this study identifies several centrosome-associated proteins as novel SDCCAG8 interaction partners, and provides new insights into the function of SDCCAG8 at this structure. © 2016 Airik et al. This.

Background: Sexual dysfunction such as erectile dysfunction (ED) may be a hidden agenda, but, it should be dealt with by family physicians in primary care. We investigated the prevalence of ED and utilization of sexual consultation practice among community family physicians. Methods: We analyzed the subjects who were males aged over 30 and married who visited 10 community family clinics around Seoul, Korea and completed questionnaires related to erectile function and utilization of sexual consultation service from May 9 to 28 2009. ED was designated if the 5-item version of international index of erectile dysfunction (IIEF5) scores were less than 17. Results: The average age of the responders was 45.6 years. The prevalence of ED was 43.3% and increased according to age, chronic disease, low educational history and low family income. Almost all of the mild ED patients answered that they needed sexual consultation. But, half of them had no plan to have a sexual consultation. Odds ratios (ORs) with 95% confi dence intervals (CIs) for having a sexual consultation or not according to variables were calculated with logistic regression. More severe ED (OR = 0.875; 95% CI, 0.827 to 0.926), existence of chronic disease (OR = 1.828; 95% CI, 1.026 to 3.260), inferior education (OR = 0.395; 95% CI, 0.196 to 0.796), and lower income (OR = 0.326; 95% CI, 0.124 to 0.857) were the factors which infl uenced to have a sexual consultation with a family physician. Conclusion: The prevalence of ED in family clinic was over 40%, but the utilization of sexual consultations was under 50%. We need to develop intervention strategies for more sexual counseling practice according to educational history, family incomes and status of ED in community family medicine clinics.