Abstract
MicroRNA-27a (miR-27a) upregulation has been identified in diabetes, but the pathogenesis of miR-27a in renal tubulointerstitial fibrosis (TIF) in diabetic nephropathy (DN) has not been elucidated. Herein, we found that high glucose stimulated miR-27a expression, which directly inhibited PPARγ and promoted fibrosis in NRK-52E cells. The functional relevance of miR-27a-dependent PPARγ decrease was proven by inhibition or overexpression of miR-27a both in vitro and in streptozotocin-induced diabetic rats. MiR-27a, via repression of PPARγ, activates the TGF-β/Smad3 signaling and contributes to the expressional changes of connective tissue growth factor (CTGF), Fibronectin and Collagen I, key mediators of fibrosis. Furthermore, we provide evidences that plasma miR-27a upregulation contributed to unfavorable renal function and increased TIF in renal tissues of diabetic rats and DN patients. Notably, miR-27a exhibited clinical and biological relevance as it was linked to elevated serum creatinine, proteinuria, urinary N-acetyl-β-D-glucosaminidase (NAG), and reduced estimated glomerular filtration rate (eGFR). Thus, we propose a novel role of the miR-27a-PPARγ axis in fostering the progression toward more deteriorated renal TIF in DN. Monitoring plasma miR-27a level and its association with PPARγ can be used to reflect the severity of renal TIF. Targeting miR-27a could be evaluated as a potential therapeutic approach for DN.
Highlights
Diabetes has become a major public issue worldwide
To further elucidate whether PPARγ is a direct target of miR-27a, we used a dual-luciferase reporter assay to detect whether miR-27a directly interacted with www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget the 3′-untranslated region (3′-untranslated regions (UTR)) of PPARγ mRNA
These results suggest that miR-27a directly suppresses PPARγ and induces fibrosis in high glucose cultured NRK-52E cells in vitro
Summary
Diabetes has become a major public issue worldwide. As the leading cause of end-stage renal disease (ESRD) [1], diabetic nephropathy (DN) leads to chronic renal failure and affects approximately 15–25% of type 1 diabetic patients and 30–40% of type 2 diabetic patients [2], even though numerous interventions, such as tight glycemic control, ideal control of blood pressure and blood lipid, and the rennin-angiotensin system inhibition, are extensively used. Why does the prevalence of diabetic nephropathy still remain high and why do many patients on rennin-angiotensin system inhibitors still progress to ESRD?. Fibrosis is the final common pathway of ESRD caused by chronic kidney diseases for various reasons [3]. The pathogenic role of tubulointerstitial fibrosis (TIF) in relation to declined renal function in DN warrants exploration. Tubules are vulnerable and injurious to various stimuli, like hypoxia, inflammation, www.impactjournals.com/oncotarget high glucose microenvironment and immune factors [4, 5]. The mechanism is presently not clear and may be related to multiple factors such as immune, inflammation and epithelial cell transdifferentiation [6,7,8,9]. Elucidating the pathogenic mechanisms of TIF in DN is of great significance in improving the disease outcome
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