Mesenchymal stem cells inhibit mitochondrial fission by upregulating armadillo repeat containing 1, ameliorating oxidative stress in renal fibrosis

Abstract

Background Oxidative stress damage is the important mechanism that promotes the process of fibrosis. Whether mesenchymal stem cells (MSCs) regulate mitochondrial dynamics and oxidative stress via armadillo repeat containing 1 (ARMC1) in renal fibrosis? Methods Using proteomics analysis, compare the significant differences in renal tissue proteins before and after MSCs intervention in adenine-induced nephropathy. Using a lentiviral vector to overexpress the ARMC1 gene in HK-2 cells, with the empty vector as a control. MSCs conditioned media (MSCs-CM) was applied to TGF-β1 treated cells, and MSCs were used in a cisplatin-induced nephropathy mouse model to assess mitochondrial dynamics, ROS generation, antioxidant stress, and fibrosis indicators, with Mdivi-1 (a Drp1 inhibitor) and Apocynin (a selective NADPH oxidase inhibitor) as positive controls. Results Renal proteomics showed that MSCs increased ARMC1 protein in the renal tissue of adenine nephropathy (3.521 times). In vitro, MSCs-CM increased ARMC1, reduced DRP1, and enhanced OPA1 and MFN2, lowering ROS, boosting mitochondrial bioactivity, and increasing antioxidant proteins NRF2, SOD1, SOD2, and CAT while decreasing fibrosis markers α-SMA, FN, COL-I, and KIM-1, and raising E-cadherin. The indicator variations in ARMC1-OE cells and OE-Con cells were similar between subgroups; Notably, under identical treatment conditions, the shifts in indicators within ARMC1-OE cells were more significant than those observed in OE-Con cells. In cisplatin-induced nephropathy mice, MSCs, Apocynin, and Mdivi-1 improved renal function and reduced interstitial collagen deposition, inhibited mitochondrial fission, enhanced antioxidant capacity, and reduced fibrosis. However, individual interventions were found to be less effective than their combined counterparts, with the synergistic impact of MSCs and Mdivi-1 achieving the most remarkable outcomes. Conclusion MSCs have the potential to improve renal fibrosis by influencing mitochondrial dynamics and oxidative stress through the upregulation of ARMC1 expression. ARMC1 may be an effective target for anti-fibrosis.

1. Introduction

Renal fibrosis is a prevalent pathological feature observed in various chronic kidney diseases (CKD) and acute kidney injury (AKI), representing a significant challenge and focus of research in this field. The primary pathological characteristics of renal fibrosis include abnormal deposition of the extracellular matrix, infiltration of inflammatory cells, thickening of the vascular endothelium, narrowing of the lumen, and a decline in renal function, which can ultimately lead to end-stage renal disease (ESRD) [1]. Mitochondria, known as the main sites for cellular energy production, play a crucial and multifaceted role in the development of renal fibrosis. They affect the pathological processes in the kidneys through several mechanisms, including the regulation of energy metabolism, oxidative stress, cell death, and signal transduction [2].

Mitochondria are also the primary source of reactive oxygen species (ROS), which contribute to inflammation and oxidative stress—both of which are key factors in the pathological progression of fibrosis [3]. ROS can result in cell damage and apoptosis, heighten inflammatory responses, and promote the release of fibrosis-related factors such as TGF-β1. These factors, in turn, stimulate the proliferation of fibroblasts and the synthesis of collagen [4]. Targeting mitochondrial regulation has emerged as a vital research direction in the study of antifibrotic therapies.

Numerous studies have proved that MSCs themselves or their derivatives have significant potential in delaying organ fibrosis, making MSCs one of the most promising options in antifibrotic therapy [5–7]. MSCs are advantageous due to their diverse sources, easy accessibility, ability to secrete multiple cytokines, and their properties that promote immune regulation, angiogenesis, and anti-inflammatory responses, all while maintaining a high safety profile [8, 9]. In the adenine-induced rat renal fibrosis model, renal proteomics analysis showed that MSCs intervention significantly increas...