In the last decade, miRNAs have received substantial attention as potential players of diabetes microvascular complications, affecting the kidney, the retina, and the peripheral neurons. Compelling evidence indicates that abnormally expressed miRNAs have pivotal roles in key pathogenic processes of microvascular complications, such as fibrosis, apoptosis, inflammation, and angiogenesis. Moreover, clinical research into innovative both diagnostic and prognostic tools suggests circulating miRNAs as possible novel noninvasive markers of diabetes microvascular complications. In this review, we summarize current knowledge and understanding of the role of miRNAs in the injury to the microvascular bed in diabetes and discuss the potential of miRNAs as clinical biomarkers of diabetes microvascular complications.

Heat shock proteins (HSPs) are a large family of proteins highly conserved throughout evolution because of their unique cytoprotective properties. Besides assisting protein refolding and regulating proteostasis under stressful conditions, HSPs also play an important role in protecting cells from oxidative stress, inflammation, and apoptosis. Therefore, HSPs are crucial in counteracting the deleterious effects of hyperglycemia in target organs of diabetes vascular complications. Changes in HSP expression have been demonstrated in diabetic complications and functionally related to hyperglycemia-induced cell injury. Moreover, associations between diabetic complications and altered circulating levels of both HSPs and anti-HSPs have been shown in clinical studies. HSPs thus represent an exciting therapeutic opportunity and might also be valuable as clinical biomarkers. However, this field of research is still in its infancy and further studies in both experimental diabetes and humans are required to gain a full understanding of HSP relevance. In this review, we summarize current knowledge and discuss future perspective.

A functionally active endocannabinoid system is present within the kidney. The cannabinoid receptor type 2 (CB2) is expressed by both inflammatory cells and podocytes, and its activation has beneficial effects in experimental diabetic nephropathy. To further explore the role of CB2 in diabetic nephropathy, we studied renal functional and structural abnormalities in streptozotocin-induced diabetic CB2 knockout mice. In diabetic mice, deletion of the CB2 receptor albuminuria, the downregulation of podocin and nephrin, mesangial expansion, overexpression of extracellular matrix components, monocyte infiltration, and reduced renal function were all exacerbated. To investigate the relative contributions of podocytes and monocytes to the phenotype of diabetic knockout mice, bone marrow transplantation experiments were performed. The lack of CB2 on bone marrow-derived cells was shown to be important in driving the enhanced glomerular monocyte accrual found in diabetic knockout mice. Absence of CB2 on resident glomerular cells had a major role in worsening diabetic nephropathy, both functional and structural abnormalities, likely by enhanced MCP-1 and CB1 signaling. Studies in cultured podocytes demonstrated that CB2 expression is not altered by a high glucose milieu but is downregulated by mechanical stretch, mimicking glomerular capillary hypertension. Thus, CB2 deletion worsens diabetic nephropathy, independent of bone marrow-derived cells.Diabetic nephropathy (DN) is characterized by increased glomerular permeability to proteins and excessive extracellular matrix (ECM) deposition in the mesangium.1 Both hyperglycemia and hypertension are key determinants in the development of DN.2 In addition, increasing evidence suggests that a low-grade inflammatory response also has a role in disease etiology. In particular, the potent chemokine monocyte chemoattractant protein 1 (MCP-1) is an important mediator of both functional and structural abnormalities of the diabetic kidney. 3 The slit diaphragm, a junction connecting foot processes (FP) of neighboring podocytes, represents the major restriction site to protein filtration. 4 In human DN, there is a downregulation of the slit diaphragm proteins, nephrin, and podocin, and diabetes-related insults, such as advanced glycated products, MCP-1, and mechanical stretch, which mimics glomerular capillary hypertension, downregulate nephrin in cultured podocytes. 5, 6 and 7 Endocannabinoids (EC), anandamide (AEA) and 2-arachidonoylglycerol (2-AG), bind to two G-proteincoupled seven transmembrane cannabinoid receptors named CB1 and CB2. In experimental diabetes, the CB1 is overexpressed by podocytes, and CB1 blockade ameliorates albuminuria and nephrin loss. 8 The CB2 is mainly expressed by cells of hematopoietic origin including monocytes-macrophages, 9 and CB2 activation is protective in animal models of chronic inflammatory diseases, such as atherosclerosis 10 and liver fibrosis, 11 whereas CB2 deletion exacerbates tissue damage by enhancing inflammatory, oxidative, and fibrotic...

The single-nucleotide polymorphism (SNP) rs10503253, located within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2, was recently identified as genome-wide significant for schizophrenia (SZ), but is of unknown function. We investigated the neurocognitive effects of this CSMD1 variant in vivo in patients and healthy participants using behavioral and imaging measures of brain structure and function. We compared carriers and non-carriers of the risk 'A' allele on measures of neuropsychological performance typically impaired in SZ (general cognitive ability, episodic and working memory and attentional control) in independent samples of Irish patients (n = 387) and controls (n = 171) and German patients (205) and controls (n = 533). Across these groups, the risk 'A' allele at CSMD1 was associated with deleterious effects across a number of neurocognitive phenotypes. Specifically, the risk allele was associated with poorer performance on neuropsychological measures of general cognitive ability and memory function but not attentional control. These effects, while significant, were subtle, and varied between samples. Consistent with previous evidence suggesting that CSMD1 may be involved in brain mechanisms related to memory and learning, these data appear to reflect the deleterious effects of the identified 'A' risk allele on neurocognitive function, possibly as part of the mechanism by which CSMD1 is associated with SZ risk.

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