Transforming Growth Factor β1 (TGF-β1) Enhances Expression of Profibrotic Genes through a Novel Signaling Cascade and MicroRNAs in Renal Mesangial Cells

Abstract

Increased TGF‐β1 expression in glomerular mesangial cells (MC) augments extracellular matrix accumulation, hypertrophy and pro‐fibrotic genes during the progression of diabetic nephropathy (DN), a debilitating renal complication of diabetes. microRNAs (miRNAs) play key roles in the pathogenesis of DN by modulating the actions of TGF‐β1 to enhance the expression of pro‐fibrotic genes like collagen. In this study, we found a significant decrease in the expression of key members of the miR‐130 and miR‐30 families in mouse MC (MMC) treated with TGF‐β1. In parallel there was a decrease in host genes 2610318N02RIK (RIK, miR‐130b host gene) and NF‐YC (miR‐30e* host gene), suggesting host gene‐dependent expression of these miRNAs. TGF‐β receptor1 (TGF‐βR1), was identified as a target of miR‐130b. Interestingly, the RIK promoter contains three NF‐YC binding sites and was regulated by NF‐YC, a potential target of miR‐216a which was also up‐regulated by TGF‐β1. Therefore, a novel cascade, ↑TGF‐β1>↑miR‐216a>↓NF‐YC>↓RIK (↓miR‐130b) may up‐regulate TGF‐βR1 to augment expression of TGF‐β1 target fibrotic genes. miR‐130 and miR‐30e* were down‐regulated, whereas TGF‐βR1, as well as the pro‐fibrotic genes COLIVa1, COLXIIa1, CTGF and PAI‐1 were up‐regulated by TGF‐β1 in MMC and in the glomeruli of streptozotocin injected diabetic mice, supporting in vivo relevance. Together, these results demonstrate a novel miRNA‐ and their host gene‐mediated cascade initiated by TGF‐β1 which results in the up‐regulation of pro‐fibrotic factors such as TGF‐βR1 and collagens associated with the progression of DN. Grant Funding Source: Supported by NIH R01 DK081705 and ADA 7‐10‐MI‐07

Mini-review: emerging roles of microRNAs in the pathophysiology of renal diseases

“…Interestingly, the downregulation of let-7a-3 in DN was associated with promoter DNA hypermethylation, suggesting an epigenetic regulatory mechanism (114). TGF-␤1-induced decrease of miR130b was shown to upregulate its target, TGF-␤1R1, in MC through mechanisms involving a decrease in Ybx1/NFYC targeted by miR-216a, thus revealing another miRNA-mediated amplifying cascade (17). miR-135a, which promotes ECM accumulation by targeting a transient receptor potential cation channel, subfamily C, member 1 (TRPC1), was enriched in serum and renal tissue from patients with DN and db/db mice (50).…”

Multiple obesity related mechanisms of kidney disease

“…Transformirajući faktor rasta beta (TGFß) glavni je posrednik ubrzanoga starenja, odnosno fibroziranja bubrega, koji stimulira nakupljanje ekstracelularnog matriksa, čime se narušava normalan rad bubrega. Povišena razina TGFß-a nalazi se u stanjima inzulinske rezistencije i pretilosti, a dobro je poznato da leptin stimulira proliferaciju TGFß-a u endotelnim stanicama glomerula 13 .…”

“…The most relevant characteristic of premature cell and tissue aging is reduced methylation (hypomethylation) due to restricted dietary intake of foods rich in methyl groups (folate, bogate metilnim skupinama u dječjoj dobi ima utjecaj na DNA metilaciju i povećava rizik od nepovoljnih ishoda u kasnijoj odrasloj dobi, uključujući i razvoj zloćudnih bolesti, ubrzane ateroskleroze, arterijske hipertenzije i pretilosti. Nedostatna je "metilacija" karakteristika preuranjenoga starenja stanica i bolesti vezanih za pretilost 13 .…”

“…kidney fibrozation, which stimulates accumulation of extracellular matrix, thus interfering with normal kidney function. Elevated TGFβ level is found in the states of insulin resistance and obesity, while leptin is known to stimulate TGFβ proliferation in glomerular endothelial cells 13 .…”

“…Deficient intake of diet high in methyl groups in childhood influences DNA methylation and increases the risk of unfavorable outcomes later in life, including development of malignant diseases, accelerated atherosclerosis, arterial hypertension, and obesity. Inadequate methylation is a characteristic of premature cell aging and obesity related diseases 13 .…”