Role of microRNAs in Obesity-Related Kidney Disease

Abstract

Obesity is a major global health problem and is associated with a significant risk of renal function decline. Obesity-related nephropathy, as one of the complications of obesity, is characterized by a structural and functional damage of the kidney and represents one of the important contributors to the morbidity and mortality worldwide. Despite increasing data linking hyperlipidemia and lipotoxicity to kidney injury, the apprehension of molecular mechanisms leading to a development of kidney damage is scarce. MicroRNAs (miRNAs) are endogenously produced small noncoding RNA molecules with an important function in post-transcriptional regulation of gene expression. miRNAs have been demonstrated to be important regulators of a vast array of physiological and pathological processes in many organs, kidney being one of them. In this review, we present an overview of miRNAs, focusing on their functional role in the pathogenesis of obesity-associated renal pathologies. We explain novel findings regarding miRNA-mediated signaling in obesity-related nephropathies and highlight advantages and future perspectives of the therapeutic application of miRNAs in renal diseases.

Keywords: hyperlipidemia; inflammation; kidney; lipotoxicity; microRNAs; obesity; obesity-related kidney disease; renoprotection; therapeutic agents.

Figure 1

miRNAs biogenesis and post-transcriptional gene regulation mechanisms. In the nucleus, genomic DNA is transcribed by RNA polymerase II to form a pri-miRNA. pri-miRNA is recognized and cleaved by the complex composed of RNase III Drosha and DGCR8 to generate pre-miRNA. Pre-miRNA is exported into the cytoplasm by exportin-5 RanGTP and further cleaved by Dicer-TRBP to generate miRNA duplex. This duplex is loaded onto the pre-RISC complex, where consequently only one strand (“guide strand”) will stay to form the RISC complex. The guide strand will lead the mature RISC complex to a nearby 3′ UTR complementary sequence of the target mRNA. If miRNA and its target mRNA establish the perfect match, a direct mRNA degradation will occur (A). Alternatively, an imperfect match between miRNA and its target mRNA will lead to a translational repression and a decrease in protein levels of the target gene (B). In certain conditions, miRNAs can activate translation of target mRNA (C). miRNAs could also be found in the nucleus regulating gene transcription (D), either by silencing or activating target genes through miRNA-binding sites within the gene promoters. DGCR8, DiGeorge syndrome critical region 8 cofactor; TRBP, transactivating response RNA-binding protein.

Figure 2

Effects of adiposity on normal renal function. Abnormal hypertrophy of adipose tissue in obesity may lead to changes in expression of different adipocytokines, inflammatory and profibrotic parameters, as well as the ectopic accumulation of circulating lipids in the kidney, contributing to tissue damage through a process known as lipotoxicity. RPTECs, podocytes, and mesangial cells are not equipped with an adequate machinery to handle large lipid overloads; thus, accumulation of lipids in these cells will lead to a cell dysfunction accompanied by the generation of ROS, impairment of renin–angiotensin–aldosterone activity, secretion of proinflammatory and profibrotic factors, and insulin resistance. These self-perpetuating secondary events may subsequently lead to a further damage of renal cells and progressive impairment of kidney structure and function. RPTECs, renal proximal tubular epithelial cells; ROS, reactive oxygen species; ECM, extracellular matrix.