Diabetic nephropathy--emerging epigenetic mechanisms

Abstract

Diabetic nephropathy (DN), a severe microvascular complication frequently associated with both type 1 and type 2 diabetes mellitus, is a leading cause of renal failure. The condition can also lead to accelerated cardiovascular disease and macrovascular complications. Currently available therapies have not been fully efficacious in the treatment of DN, suggesting that further understanding of the molecular mechanisms underlying the pathogenesis of DN is necessary for the improved management of this disease. Although key signal transduction and gene regulation mechanisms have been identified, especially those related to the effects of hyperglycaemia, transforming growth factor β1 and angiotensin II, progress in functional genomics, high-throughput sequencing technology, epigenetics and systems biology approaches have greatly expanded our knowledge and uncovered new molecular mechanisms and factors involved in DN. These mechanisms include DNA methylation, chromatin histone modifications, novel transcripts and functional noncoding RNAs, such as microRNAs and long noncoding RNAs. In this Review, we discuss the significance of these emerging mechanisms, how they mediate the actions of growth factors to augment the expression of extracellular matrix and inflammatory genes associated with DN and their potential usefulness as diagnostic biomarkers or novel therapeutic targets for DN.

Figure 1.. Emerging molecular mechanisms of diabetic nephropathy.

Diabetic conditions induce the expression of growth factors such as TGF-β1 and angiotensin II, cytokines and AGEs to promote inflammation, fibrosis and hypertrophy, which contribute to the progression of diabetic nephropathy. These factors stimulate various signal transduction mechanisms that activate downstream transcription factors. They can also affect DNA methylation and histone modifications, which result in increased chromatin accessibility to transcription factors near pathological genes in renal cells. Coordinated interactions between transcription factors and epigenetic mechanisms can increase the expression of not only coding RNAs, but also noncoding RNAs such as microRNAs and lncRNAs. Furthermore, microRNAs and lncRNAs can also increase the expression of pathological genes via post-transcriptional mechanisms. Notably, the induction of key coding genes and proteins, lncRNAs and microRNAs can also ‘lock’ open chromatin states to create persistent expression of genes, which could be one mechanism of metabolic memory. Abbreviations: AGE, advanced glycation end-product; lncRNA, long noncoding RNA.

Figure 2.. Regulation of gene transcription in DN mediated by histone lysine modifications.

Diabetic conditions activate transcription factors through signal transduction mechanisms to increase gene expression. These signalling mechanisms can also alter histone lysine modifications to increase chromatin accessibility, that is from compact (suppressed) to open (active) chromatin. Two types of histone modifications are proposed: histone lysine acetylation (Kac) and histone lysine methylation (Kme). A dynamic balance between active and repressive marks can create open chromatin states near DN-related genes, increase transcription factor accessibility, and promote expression of genes associated with inflammation and fibrosis. These signalling events and epigenetic mechanisms also promote the expression of noncoding RNAs and, together, can lead to persistently open chromatin states and unchecked gene expression, which can be a mechanism underlying metabolic memory. Several approaches can interrupt these processes, which could form the basis of new therapeutic targets for DN. a | Activation of histone acetyltransferases mediates increases in H3Kac (especially H3K9ac), which increases chromatin accessibility to transcription factors. b | Kme can be induced by HMTs and erased by KDMs. Diabetic conditions can downregulate repressive H3K9 HMTs to decrease H3K9me2/3 levels, or activate permissive H3K4 HMTs to increase H3K4me1/2/3 levels near pathological genes. Activation of some H3K9 KDMs may also demethylate H3K9me3. Abbreviations: Ac, acetylation; DN, diabetic nephropathy; HDAC, histone deacetylase; HMT, histone methyltransferase; KDM, histone lysine demethylase; lncRNA, long noncoding RNA; Me, methylation; P, phosphorylation.