Argirein alleviates diabetic nephropathy through attenuating NADPH oxidase, Cx43, and PERK in renal tissue.
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 (ET(A)) 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 ET(A), 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.
Research Division of Pharmacology, China Pharmaceutical University, 24 Tongjia Lane, Nanjing 210009, China.
C
C
Hu
X D
XD
Cong
De-Zai
DZ
Dai
Y
Y
Zhang
G L
GL
Zhang
Y
Y
Dai
D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology / Q000627:therapeutic use*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D001806:Blood Urea Nitrogen; D018031:Connexin 43 / Q000235:genetics*; D003404:Creatinine / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology / Q000652:urine; D003928:Diabetic Nephropathies / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology / Q000652:urine; D019332:Endothelin-1 / Q000235:genetics; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011507:Proteinuria / Q000188:drug therapy / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
D000880:Anthraquinones; D016282:Aspartic Acid Endopeptidases; D001786:Blood Glucose; D018031:Connexin 43; D003404:Creatinine; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors; D006146:Guanidines; D008666:Metalloendopeptidases; D019255:NADPH Oxidases; D020030:Nitric Oxide Donors; D047493:PPAR alpha; D021122:Protein Subunits; D044022:Receptor, Endothelin A; D019892:eIF-2 Kinase; C558481:argirhein; C004479:pimagedine
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