Emerging Role of Long Non-Coding RNAs in Diabetic Vascular Complications

Chronic metabolic disorders such as obesity and diabetes are associated with accelerated rates of macrovascular and microvascular complications, which are leading causes of morbidity and mortality worldwide. Further understanding of the underlying molecular mechanisms can aid in the development of novel drug targets and therapies to manage these disorders more effectively. Long non-coding RNAs (lncRNAs) that do not have protein-coding potential are expressed in a tissue- and species-specific manner and regulate diverse biological processes. LncRNAs regulate gene expression in cis or in trans through various mechanisms, including interaction with chromatin-modifying proteins and other regulatory proteins and via posttranscriptional mechanisms, including acting as microRNA sponges or as host genes of microRNAs. Emerging evidence suggests that major pathological factors associated with diabetes such as high glucose, free fatty acids, proinflammatory cytokines, and growth factors can dysregulate lncRNAs in inflammatory, cardiac, vascular, and renal cells leading to altered expression of key inflammatory genes and fibrotic genes associated with diabetic vascular complications. Here we review recent reports on lncRNA characterization, functions, and mechanisms of action in diabetic vascular complications and translational approaches to target them. These advances can provide new insights into the lncRNA-dependent actions and mechanisms underlying diabetic vascular complications and uncover novel lncRNA-based biomarkers and therapies to reduce disease burden and mortality

Epigenetic modifications and diabetic nephropathy

Diabetic nephropathy (DN) is a major complication associated with both type 1 and type 2 diabetes, and a leading cause of end-stage renal disease. Conventional therapeutic strategies are not fully efficacious in the treatment of DN, suggesting an incomplete understanding of the gene regulation mechanisms involved in its pathogenesis. Furthermore, evidence from clinical trials has demonstrated a “metabolic memory” of prior exposure to hyperglycemia that continues to persist despite subsequent glycemic control. This remains a major challenge in the treatment of DN and other vascular complications. Epigenetic mechanisms such as DNA methylation, nucleosomal histone modifications, and noncoding RNAs control gene expression through regulation of chromatin structure and function and post-transcriptional mechanisms without altering the underlying DNA sequence. Emerging evidence indicates that multiple factors involved in the etiology of diabetes can alter epigenetic mechanisms and regulate the susceptibility to diabetes complications. Recent studies have demonstrated the involvement of histone lysine methylation in the regulation of key fibrotic and inflammatory genes related to diabetes complications including DN. Interestingly, histone lysine methylation persisted in vascular cells even after withdrawal from the diabetic milieu, demonstrating a potential role of epigenetic modifications in metabolic memory. Rapid advances in high-throughput technologies in the fields of genomics and epigenomics can lead to the identification of genome-wide alterations in key epigenetic modifications in vascular and renal cells in diabetes. Altogether, these findings can lead to the identification of potential predictive biomarkers and development of novel epigenetic therapies for diabetes and its associated complications

Differential behavior of mesangial cells derived from 12/15-lipoxygenase knockout mice relative to control mice11See Editorial by Kasinath, p. 1918.

Differential behavior of mesangial cells derived from 12/15-lipoxygenase knockout mice relative to control mice.BackgroundThe 12/15-lipoxygenase (12/15-LO) enzyme has been implicated in the pathogenesis of diabetic nephropathy since lipoxygenase products induce cellular hypertrophy and extracellular matrix deposition in mesangial cells. In this study, in order to determine the potential in vivo functional role of 12/15-LO in kidney disease, we compared mouse mesangial cells (MMCs) derived from 12/15-LO knockout mice with those from genetic control wild-type mice.MethodsMMCs were isolated from wild-type and 12/15-LO knockout mice. Cellular growth, activation of mitogen-activated protein kinases (MAPKs), transcription factors, superoxide levels, and fibronectin expression were compared in the two cell types.ResultsLevels of the 12/15-LO product and protein were lower in MMC from 12/15-LO knockout relative to wild-type. MMCs from 12/15-LO knockout mice grew slower than wild-type cells, and also showed lower rates of tritiated thymidine and leucine incorporation (21% and 15% of wild-type, respectively, P < 0.001). Levels of superoxide and the matrix protein fibronectin were also lower in 12/15-LO knockout mice cells. Serum and angiotensin II (Ang II)-stimulated activities of p38 or ERK1/2 MAPKs, and cyclic adenosine monophosphate (cAMP)-responsive element binding protein (CREB) transcription factor were lower in 12/15-LO knockout relative to wild-type cells. In addition, DNA binding and transcriptional activities of activated protein-1 (AP-1) and CREB were lower in 12/15-LO knockout cells. Furthermore, stable 12/15-LO overexpression in MMC led to reciprocal increase in p38 MAPK activation and fibronectin expression.ConclusionThe differential activation of oxidant stress, specific signaling pathways, transcription factors, and growth and matrix genes may lead to reduced growth and growth factor responses in 12/15-LO knockout versus wild-type MMCs. These results provide ex vivo functional evidence for the first time that 12/15-LO activation plays a key role in mesangial cell responses associated with renal diseases such as diabetic nephropathy

Challenges and Successes with Food Resource Referrals for Food-Insecure Patients with Diabetes

Clinics increasingly screen patients for food insecurity, but little is known about the efficacy of referring food-insecure patients to community-based food resources. To evaluate the implementation of a tailored community food resource referral program in a safety-net diabetes clinic. We conducted semistructured phone interviews with food-insecure patients participating in a screening and referral program in a diabetes clinic affiliated with a safety-net hospital. In this qualitative study, we describe barriers to and facilitators of successful food resource referrals from the patient's perspective. The prevalence of food insecurity was high (60%). Provision of written and verbal information alone about community food resources resulted in low linkage rates (0%-4%), even with individually tailored referrals. Misperceptions about eligibility, fears around government program registration, inaccessibility, lack of information retention, competing priorities, an inability to cook, stigma, and a perceived sense of stability with existing food support were major barriers to use. Personnel-guided, in-clinic enrollment to a food resource facilitated a higher connection rate (31%). Results of this study suggest that screening for food insecurity followed by a list of food resources for those screening positive may not adequately address patient barriers to using community-based food resources. For food insecurity screening programs in the clinical setting to be effective, systems must not only distribute food resource information but also assist patients in enrollment processes

Lessons Learned from Implementation of the Food Insecurity Screening and Referral Program at Kaiser Permanente Colorado

Traditionally, health care systems have addressed gaps in patients' diet quality with programs that provide dietary counseling and education, without addressing food security. However, health care systems increasingly recognize the need to address food security to effectively support population health and the prevention and management of diet-sensitive chronic illnesses. Numerous health care systems have implemented screening programs to identify food insecurity in their patients and to refer them to community food resources to support food security. This article describes barriers encountered and lessons learned from implementation and expansion of the Kaiser Permanente Colorado's clinical food insecurity screening and referral program, which operates in collaboration with a statewide organization (Hunger Free Colorado) to manage clinic-to-community referrals. The immediate goals of clinical screening interventions described in this article are to identify households experiencing food insecurity, to connect them to sustainable (federal) and emergency (community-based) food resources, to alleviate food insecurity, and to improve dietary quality. Additional goals are to improve health outcomes, to decrease health care utilization, to improve patient satisfaction, and to better engage patients in their care