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

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 (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.

ER Stress, P66shc, and P-Akt/Akt Mediate Adjuvant-Induced Inflammation, Which Is Blunted by Argirein, a Supermolecule and Rhein in Rats

“…Thus, a recovery of abnormal MMP-2 is resultant from suppression of NADPH oxidase by argirein and rhein, along with a reduction in inflammatory edema. Hyperexpression of NADPH oxidase found in diabetic renal tissue is substantially suppressed by argirein leading to alleviation of lesions in diabetic nephropathy in streptozotocin-injected rats [10].…”

“…As a consequence, pharmacological effects of argirein are dependent on both anti-inflammatory activity of rhein and the NO offering activity of L-arginine, and the latter is beneficial to recovery of dysfunctional vascular endothelium in the inflamed tissue. Argirein attenuates diabetic nephropathy in streptozotocin-injected rats through suppressing upregulated pro-inflammatory biomarkers such as NADPH oxidase and junctional communication molecule Cx43 (connexin 43) in renal tissue [10]. The compromised cardiac function suffering from isoproterenol-injected rat heart is significantly alleviated by argirein by normalizing the aberrant cytokines and calcium handling protein FKBP12.6 in the myocardium [11].…”

Endoplasmic reticulum stress mediating downregulated StAR and 3-beta-HSD and low plasma testosterone caused by hypoxia is attenuated by CPU86017-RS and nifedipine

“…Cell protection in the hypoxic testes could be achieved by upregulation of PERK through reducing translation contributing to reduction of critical regulatory proteins which promotes activation of transcription factors such as NFκ-B under cellular stress [33]. Important consequence of PERK- eIF2α pathway could take place in the testis damaged by hypoxia exposure, the same as those showed in diabetic nephropathy which is characterized by upregulation of PERK in renal tissue [34]. …”

CPU86017-RS attenuate hypoxia-induced testicular dysfunction in mice by normalizing androgen biosynthesis genes and pro-inflammatory cytokines

“…* To whom correspondence should be addressed. E-mail dezaidai@vip.sina.com Received 2011-08-22 Accepted 2011- [11][12][13][14][15][16][17][18] cardiovascular systems [7] , and possibly damages the reproductive system as well. A decline in the ability of conceive has frequently been noticed in population lived in highland area.…”

“…Matrix metalloprotease (MMPs) are the most important proteases participating in extracellular matrix degradation and remodeling and MMP9 takes an important part in the maintenance of the normal structure and function of the seminiferous tubules. Intercellular gap junction com-www.chinaphar.com Zhang GL et al Acta Pharmacologica Sinica npg munication is operated by a family of proteins known as connexins, among them connexin 43 (Cx43) is the most abundant and extensively distributed of the connexins and it is known to be affected in disease [13,14] . An alteration of Cx43 is concerned in abnormal function and structure of the testis [15] .…”