Abstract
The aim of this study was to investigate the effect and possible mechanism of Astragaloside IV (AS-IV) on retarding the progression of diabetic nephropathy (DN) in a type 2 diabetic animal model, db/db mice. Eight-week-old male db/db diabetic mice and their nondiabetic littermate control db/m mice were used in the present study. AS-IV was administered to the db/db mice by adding it to standard feed at a dose of 1g/kg for 12 weeks. Renal injury was assessed by urinary albumin excretion (UAE) and Periodic acid-Schiff staining. The protein expression levels of mitochondrial quality-control-associated proteins were evaluated using Western blotting and immunohistochemical staining analysis. At the end of the experiment, db/db mice showed overt renal injury, as evidenced by increased UAE, increased urinary N-acetyl-β-D-glucosaminidase (NAG), expansion of mesangial matrix, and increased renal tubular area. AS-IV administration significantly reduced UAE and urinary NAG and ameliorated the renal pathologic injury seen in db/db mice. Furthermore, the expression of dynamin-related protein 1 (Drp-1), mitochondrial fission protein 1 (Fis-1), and mitochondrial fission factor (MFF), the main regulators of mitochondrial fission, was significantly increased in db/db mice. Moreover, PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy was abnormally activated in db/db mice. AS-IV significantly reduced renal Drp-1, Fis-1, and MFF expression and downregulated PINK1/Parkin-mediated mitophagy in db/db mice. However, mitochondrial biogenesis and mitochondrial fusion-associated protein levels were not significantly different between db/m and db/db mice in our study, with or without AS-IV treatment. In conclusion, administration of AS-IV could retard DN progression in type 2 diabetes mice, which might be associated with restoration of the mitochondrial quality control network.
Highlights
According to the International Diabetes Federation (IDF), the estimated diabetes prevalence for adults between the ages of 20 and 79 worldwide for 2015 was 415 million; the disease is expected to affect 642 million people by 2040 [1]
Our results suggest that the renoprotective effect of Astragaloside IV (AS-IV) on Diabetic nephropathy (DN) in the state of type 2 diabetes might be associated with the modulation of the mitochondrial quality control network, which was deranged in db/db mice
We examined the effect of AS-IV on retarding DN progression in an experimental animal model of type 2 diabetes, db/db mice
Summary
According to the International Diabetes Federation (IDF), the estimated diabetes prevalence for adults between the ages of 20 and 79 worldwide for 2015 was 415 million; the disease is expected to affect 642 million people by 2040 [1]. The molecular mechanisms implicated in the pathogenesis and progression of DN remain unclear, increasing evidence indicates that disturbances in mitochondrial homeostasis might be important in the development and progression of DN [3]. Mitochondria are dynamic organelles that play many essential roles in the regulation of energy metabolism, signal transduction, cell differentiation, cell proliferation, and cell death [4]. A growing body of evidence shows that mitochondrial dysfunction plays a pivotal role in the pathogenesis of various kidney diseases [5]. Emerging evidence suggests that disturbances in the mitochondrial quality control network might be important in DN pathogenesis [7]. The alteration of mitochondrial quality control regulation in the kidney of a type 2 diabetes animal model is not well defined and needs to be investigated
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