MicroRNA-29a Attenuates Diabetic Glomerular Injury through Modulating Cannabinoid Receptor 1 Signaling.

Cheng Ho,Chun-Wu Tung,Chun-Liang Lin,Ya-Hsueh Shih,Yung-Chien Hsu,Shun-Chen Huang

doi:10.3390/molecules24020264

Abstract

Diabetic nephropathy often leads to end-stage renal disease and life-threatening morbidities. Simple control of risk factors is insufficient to prevent the progression of diabetic nephropathy, hence the need for discovering new treatments is of paramount importance. Recently, the dysregulation of microRNAs or the cannabinoid signaling pathway has been implicated in the pathogenesis of various renal tubulointerstitial fibrotic damages and thus novel therapeutic targets for chronic kidney diseases have emerged; however, the role of microRNAs or cannabinoid receptors on diabetes-induced glomerular injuries remains to be elucidated. In high-glucose-stressed renal mesangial cells, transfection of a miR-29a precursor sufficiently suppressed the mRNA and protein expressions of cannabinoid type 1 receptor (CB1R). Our data also revealed upregulated CB1R, interleukin-1β, interleukin-6, tumor necrosis factor-α, c-Jun, and type 4 collagen in the glomeruli of streptozotocin (STZ)-induced diabetic mice, whereas the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) was decreased. Importantly, using gain-of-function transgenic mice, we demonstrated that miR-29a acts as a negative regulator of CB1R, blocks the expressions of these proinflammatory and profibrogenic mediators, and attenuates renal hypertrophy. We also showed that overexpression of miR-29a restored PPAR-γ signaling in the renal glomeruli of diabetic animals. Collectively, our findings indicate that the interaction between miR-29a, CB1R, and PPAR-γ may play an important role in protecting diabetic renal glomeruli from fibrotic injuries.

Highlights

Diabetic nephropathy, which is the leading cause of end-stage renal disease globally, often leads to life-threatening morbidities [1]
We used streptozotocin (STZ)-treated mice in this study to further investigate the potential roles of miR-29a and cannabinoid type 1 receptor (CB1R) signaling in diabetic glomerular damage
Improvement of renal hypertrophy as evidenced by decreased kidney-to-body weight ratio was observed in miR-29a transgenic mice after induction of diabetes, which was consistent with our previous experimental results [20] (Table 1)

Summary

Introduction

Diabetic nephropathy, which is the leading cause of end-stage renal disease globally, often leads to life-threatening morbidities [1]. Despite the significant effort that has been devoted to exploring the pathogenic factors, there are still no effective treatments for preventing or delaying the progression of diabetic kidney failure. This implies that there may be additional unknown mediators and mechanisms that need to be investigated. The cannabinoid signaling reportedly regulates inflammatory and fibrotic reactions among various tissues [6,7,8,9,10]. Pharmacological inhibition or genetic deletion of CB1R has been shown to decrease fibrogenesis and improve survival of mice with bleomycin-induced pulmonary fibrosis [7]. CB1R overexpression or CB2R deletion was shown to induce podocytopathy and proteinuria in vivo [15,16], the role of CB1R in diabetes-mediated glomerular injuries has not been fully elucidated

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Results

Discussion

Conclusion