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Argirein alleviates diabetic nephropathy through attenuating NADPH oxidase, Cx43, and PERK in renal tissue

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Abstract

Diabetic nephropathy (DN) due to microvascular complication is a serious status characterized by continuously progressive until occurrence of the end stage of renal disease. It is attractive to investigate further mechanisms underlying the entity of DN and new drug discovery. We hypothesized that the entity of DN is inflammatory and is characterized by upregulated inflammatory/pro-inflammatory factors such as peroxisome proliferator-activated receptor alpha, NADPH oxidase, endoplasmic reticulum stress (ER stress), and endothelin receptor A (ETA) and downregulated connexin 43 (Cx43) in the kidney. Aminoguanidine is a special blocker to advanced glycation end products and argirein, a new compound contains a molecule of rhein linked to l-arginine by a hydrogen bond. Rhein possesses anti-inflammatory activity and has been chemically modified to produce a new compound diacerein launched in European market for treating osteoarthritis. Argirein with two active molecules rhein and l-arginine may be effective in suppressing the inflammatory cytokines contributing to the pathogenesis of DN. With a single injection of streptozotocin 65 mg/kg, ip in rats, early diabetic nephropathy was produced and revealed as an increased microalbuminuria, elevated creatinine and urea in serum, associated with upregulation of mRNA and protein of NADPH oxidase p22phox, p47phox, and p67phox and ETA, upregulated PKR-like eukaryotic initiation factor 2α kinase (PERK), and downregulated Cx43 in the renal tissue. Upregulation of PERK suggested that there is an ER stress involved in the diabetic kidney, along with an increase in inflammatory/pro-inflammatory factors indicating an entity of chronic inflammation. Abnormalities of biomarkers were blunted by either aminoguanidine or argirein significantly. The new compound argirein is potential in alleviating and retarding microvascular complications of diabetes such as DN in clinical settings.

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Abbreviations

AGEs:

Advanced glycation end products

AMG:

Aminoguanidine

Cx40:

Connexin 40

Cx43:

Connexin 43

DM:

Diabetes mellitus

DN:

Diabetic nephropathy

ESRD:

End stage renal disease

ER:

Endoplasmic reticulum

ER stress:

Endoplasmic reticulum stress

ET:

Endothelin-1

ETA :

Endothelin receptor A

ETB :

Endothelin receptor B

Hcy:

Homocysteine

NO:

Nitric oxide

Nox1 and Nox 4:

Two catalytic subunits of NADPH oxidase

P22:

NADPH oxidase subunit p22phox

P47:

NADPH oxidase subunit p47phox

P67:

NADPH oxidase subunit p67phox

PERK:

PKR-like eukaryotic initiation factor 2α kinase

PKA:

Protein kinase A

PKCε:

Protein kinase C epsilon

PPARα:

Peroxisome proliferator-activated receptor alpha

ROS:

Reactive oxygen species

UPR:

Unfolded protein response

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 81070145) and by the National Key New Drug Innovation Program, Ministry of Science and Technology, China (No. 2009ZX09308).

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Authors and Affiliations

  1. Research Division of Pharmacology, China Pharmaceutical University, 24 Tongjia Lane, Nanjing, 210009, China

    C. Hu, De-Zai Dai, G. L. Zhang & Y. Dai

  2. Zhejiang Chinese Medical University, Hangzhou, 311401, China

    X. D. Cong & Y. Zhang

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  1. C. Hu
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  2. X. D. Cong
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  3. De-Zai Dai
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  4. Y. Zhang
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  5. G. L. Zhang
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Correspondence to De-Zai Dai.

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C. Hu and C. X. Dong equally contribute to the paper.

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Hu, C., Cong, X.D., Dai, DZ. et al. Argirein alleviates diabetic nephropathy through attenuating NADPH oxidase, Cx43, and PERK in renal tissue. Naunyn-Schmied Arch Pharmacol 383, 309–319 (2011). https://doi.org/10.1007/s00210-010-0593-7

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