Long non-coding RNA DLX6-AS1 is the key mediator of glomerular podocyte injury and albuminuria in diabetic nephropathy by targeting the miR-346/GSK-3ß signaling pathway.

Progressive albuminuria is the primary clinical symptom of diabetic nephropathy (DN), leading to a gradual decline in kidney function. DLX6-AS1 was the first reported long non-coding RNA (lncRNA) to participate in organogenesis and play crucial roles in the brain or neural cell development. Herein, we investigated the DLX6-AS1 (Dlx6-os1 in mice) role in DN pathogenesis. We found that DLX6-AS1 expression in DN patients correlated with the extent of albuminuria. Dlx6-os1 overexpression induced cellular damage and inflammatory responses in cultured podocytes through miR-346-mediated regulation of the GSK-3ß pathway. In various established diabetic and newly developed knockout mouse models, Dlx6-os1 knockdown/knockout significantly reduced podocyte injury and albuminuria. The Dlx6-os1 effects were remarkably modulated by miR-346 mimics or mutants and significantly diminished in podocyte-specific GSK-3ß-knockout mice. Thus, DLX6-AS1 (Dlx6-os1) promotes DN development by accelerating podocyte injury and inflammation through the upregulation of the GSK-3ß pathway, providing a novel molecular target for DN therapy.

RNA-binding proteins tristetraprolin and human antigen R are novel modulators of podocyte injury in diabetic kidney disease.

Diabetic kidney disease (DKD) is one of the most common complications of diabetes, and the most common cause of end-stage renal disease, for which no effective therapies are yet available. RNA-binding proteins (RBPs) play a pivotal role in epigenetic regulation; tristetraprolin (TTP) and human antigen R (HuR) competitively bind cytokine mRNAs, exert contrasting effects on RNA stability, and drive inflammation. However, RBPs' roles in diabetes-related glomerulopathy are poorly understood. Herein, we investigated whether TTP and HuR are involved in post-transcriptional regulation of podocytopathic molecules and inflammatory cytokines in DKD. In DKD patients and db/db mice, TTP expression was significantly decreased and HuR expression was increased in glomerular podocytes, concurrent with podocyte injury, histological signs of DKD, and augmented glomerular expression of interleukin (IL)-17 and claudin-1, which are targets of TTP and HuR, as evidenced by RNA immunoprecipitation. In cultured podocytes, exposure to high ambient glucose amplified HuR expression and repressed TTP expression, upregulated IL-17 and claudin-1, and promoted podocyte injury. Thus, TTP hypoactivity or HuR hyperactivity is sufficient and essential to diabetic podocytopathy. Moreover, in silico analysis revealed that several kinases govern phosphorylation and activation of TTP and HuR, and glycogen synthase kinase (GSK)-3ß activated both TTP and HuR, which harbor putative GSK-3ß consensus phosphorylation motifs. Treatment of db/db mice with a small molecule inhibitor of GSK-3ß abrogated the changes in TTP and HuR in glomeruli and mitigated the overexpression of their target genes (IL-17, claudin-1, B7-1, and MCP-1) thus also mitigating proteinuria and DKD pathology. Our study indicates that TTP and HuR are dysregulated in DKD via a GSK-3ß-mediated mechanism and play crucial roles in podocyte injury through post-transcriptional regulation of diverse genes. It also provides novel insights into DKD's pathophysiology and identifies potential therapeutic targets.

Prevalence of amblyopia among preschool children in central south China.

AIM: To determine the prevalence and factors associated with amblyopia among children aged 30-83mo in central south of China. METHODS: A population-based, cross-sectional study was conducted in children aged 30-83mo in Changsha (an urban city) and Zhangjiajie (a rural area) in central south of China. Clinical examinations including ocular alignment, ocular motility, visual acuity (VA), prism cover test, cycloplegic refraction, slit lamp examination and fundus examination were performed by trained study ophthalmologists and optometrists. Unilateral amblyopia was defined as a 2-line difference between eyes with VA<20/32 in the worse eye and with coexisting anisometropia [≥1.00 D spherical eutivalent (SE) for hyperopia, ≥3.00 D SE for myopia, and ≥1.50 D for astigmatism], strabismus, or past or present visual axis obstruction. Bilateral amblyopia was defined as VA in both eyes <20/40 (≥ 48-month-old) and <20/50 (< 48-month-old), with coexisting hyperopia ≥4.00 D SE, myopia ≤-6.00 D SE, and astigmatism ≥2.50 D, or past or present visual axis obstruction. RESULTS: There were 8042 children enrolled and 7713 children were screened. The amblyopia prevalence in children aged 30-83mo was 1.09% (95% confidence interval, 0.86%-1.35%) with no age (P=0.81), gender (P=0.46) or area distribution (P=0.93) differences. Of these, 0.68% were unilateral cases and 0.41% were bilateral cases. Underlying causes included anisometropia (40%), binocular refractive error (36%), strabismus (14%) and deprivation (10%). Hyperopia combined with astigmatism was the frequent refractive error for ametropic and anisometropic amblyopia. CONCLUSION: In this rural and urban Chinese population, 1.09% of children with 30-83mo of age had amblyopia, a prevalence rate similar to that of many other studies. Anisometropia and refractive error are the most common causes of unilateral and bilateral amblyopia respectively.

Role of Sirtuin 1 in the pathogenesis of ocular disease (Review).

Sirtuin (SIRT)1, a member of the SIRT family, is a highly conserved NAD+­dependent histone deacetylase, which has a regulatory role in numerous physiological and pathological processes by removing acetyl groups from various proteins. SIRT1 controls the activity of numerous transcription factors and cofactors, which impacts the downstream gene expression, and eventually alleviates oxidative stress and associated damage. Numerous studies have revealed that dysfunction of SIRT1 is linked with ocular diseases, including cataract, age­associated macular degeneration, diabetic retinopathy and glaucoma, while ectopic upregulation of SIRT1 protects against various ocular diseases. In the present review, the significant role of SIRT1 and the potential therapeutic value of modulating SIRT1 expression in ocular development and eye diseases is summarized.

VDR Activation Reduces Proteinuria and High-Glucose-Induced Injury of Kidneys and Podocytes by Regulating Wnt Signaling Pathway.

BACKGROUND: Diabetic nephropathy (DN) is a major cause of end-stage renal disease and proteinuria is one of the most prominent clinical manifestations. The expression of Vitamin D receptor (VDR) in patients with chronic kidney diseases was decreased, while VDR agonists could partially alleviate the proteinuria of DN in animal models. The present study was designed to determine the expression of VDR in renal tissues and its relationship with proteinuria the diabetic model db/db mice. METHODS: The regulation effects of VDR on the Wnt signaling pathway were analyzed using RNA interference and VDR agonist paricalcitol. RESULTS: With the increase in age of the db/db mice, the VDR protein and mRNA levels in renal tissues were decreased, proteinuria increased, and the protein and mRNA levels of GSK-3ß of and ß-catenin increased. Paricalcitol treatment resulted in the up-regulation of VDR and down-regulation of GSK-3ß and ß-catenin, indicating that VDR had a regulatory effect on the Wnt signaling pathway. CONCLUSION: VDR activation could reduce proteinuria of DN mice and alleviate high-glucose-induced injury of kidneys and podocytes by regulating the key molecules of Wnt signaling pathway.