Abstract
Androgen plays a pivotal role in the progression of renal fibrosis. However, whether exogenous androgen treatment to aged male rats can improve the age-related renal fibrosis was not explored. In our study, the changes of morphological structure, renal fibrosis, ultrastructure and renal function, the expressions of extracellular matrix (ECM), matrix metalloproteinases (MMPs) and its tissue inhibitors of metalloproteinases (TIMPs), the expressions of tumor growth factor β1 (TGF-β1)/Smad signaling and oxidative stress parameters as well as nuclear factor erythroid 2-related factor 2-antioxidant response element (Nrf2-ARE) signaling were tested in kidney of aged male Wistar rats after subcutaneous testosterone propionate (TP, 2 mg/kg/d, 84-day) injection. Aged rats showed significantly renal histopathological changes, increased renal fibrosis, increased thickening of the glomerular basement membrane and the Bowman’s capsule basement membrane, declined renal functional, increased ECM, lower expressions of MMP-2 and MMP-9 and higher expressions of TIMP-1 and TIMP-2 in renal tissues and higher expressions of TGF-β1/Smad signaling, as well as lower expressions of Nrf2-ARE signaling compared to young rats. TP treatment significantly improved age-related above indexes. These results suggested that TP supplement may alleviate age-related renal fibrosis via suppression of TGF-β1/Smad signaling and activation of Nrf2-ARE signaling in aged rats.
Highlights
The results showed that testosterone propionate (TP) tretment ameliorated the age-related renal histopathological change, renal function, extracellular matrix (ECM), matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs) and tumor growth factor β1 (TGF-β1)/Smad signaling as well as oxidative stress and Nrf2-ARE signaling of the aged rats
The increased expression of MMP-2 and MMP-9 and decreased expression levels of TIMP-1 and TIMP-2 in renal tissues, the inhibition of TGF-β1/ Smad signaling, as well as the activation of Nrf2-ARE signaling were found after chronic TP supplement
The results indicated that chronic supplementation of TP may act as an antifibrotic agent via suppression of TGF-β1/ Smad signaling and activation of Nrf2-ARE signaling (Fig. 8)
Summary
Oxidative stress was one of the mechanisms participated in the age-related renal fibrosis. ROS including hydrogen peroxide (H2O2), lipid peroxides (LPO), superoxide anions and hydroxyl radicals generated during normal cellular oxidative metabolism. Androgen was capable of modulating two important cellular components, namely ECM accumulation and oxidative stress, its anti-renal fibrosis characters were not explored. Based on the effects of oxidative stress on aging-related kidney fibrosis, the status of oxidative stress in organisms might be the candidate for the discrepancy when androgens were supplemented. The changes of kidney morphology and function in aged rats were observed after TP administration as well as the blocking effects in renal fibrosis of TP administration was examined by exploring the TGF-β1/Smad and the Nrf2-ARE signaling pathway
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