Hypoxic mesenchymal stem cells ameliorate acute kidney ischemia-reperfusion injury via enhancing renal tubular autophagy

Abstract

Background Acute kidney injury (AKI) is an emerging global healthcare issue without effective therapy yet. Autophagy recycles damaged organelles and helps maintain tissue homeostasis in acute renal ischemia-reperfusion (I/R) injury. Hypoxic mesenchymal stem cells (HMSCs) represent an innovative cell-based therapy in AKI. Moreover, the conditioned medium of HMSCs (HMSC-CM) rich in beneficial trophic factors may serve as a cell-free alternative therapy. Nonetheless, whether HMSCs or HMSC-CM mitigate renal I/R injury via modulating tubular autophagy remains unclear. Methods Renal I/R injury was induced by clamping of the left renal artery with right nephrectomy in male Sprague-Dawley rats. The rats were injected with either PBS, HMSCs, or HMSC-CM immediately after the surgery and sacrificed 48 h later. Renal tubular NRK-52E cells subjected to hypoxia-reoxygenation (H/R) injury were co-cultured with HMSCs or treated with HMSC-CM to assess the regulatory effects of HSMCs on tubular autophagy and apoptosis. The association of tubular autophagy gene expression and renal recovery was also investigated in patients with ischemic AKI. Result HMSCs had a superior anti-oxidative effect in I/R-injured rat kidneys as compared to normoxia-cultured mesenchymal stem cells. HMSCs further attenuated renal macrophage infiltration and inflammation, reduced tubular apoptosis, enhanced tubular proliferation, and improved kidney function decline in rats with renal I/R injury. Moreover, HMSCs suppressed superoxide formation, reduced DNA damage and lipid peroxidation, and increased anti-oxidants expression in renal tubular epithelial cells during I/R injury. Co-culture of HMSCs with H/R-injured NRK-52E cells also lessened tubular cell death. Mechanistically, HMSCs downregulated the expression of pro-inflammatory interleukin-1β, proapoptotic Bax, and caspase 3. Notably, HMSCs also upregulated the expression of autophagy-related LC3B, Atg5 and Beclin 1 in renal tubular cells both in vivo and in vitro. Addition of 3-methyladenine suppressed the activity of autophagy and abrogated the renoprotective effects of HMSCs. The renoprotective effect of tubular autophagy was further validated in patients with ischemic AKI. AKI patients with higher renal LC3B expression were associated with better renal recovery. Conclusion The present study describes that the enhancing effect of MSCs, and especially of HMCSs, on tissue autophagy can be applied to suppress renal tubular apoptosis and attenuate renal impairment during renal I/R injury in the rat. Our findings provide further mechanistic support to HMSCs therapy and its investigation in clinical trials of ischemic AKI.

Inhibition of PLK3 Attenuates Tubular Epithelial Cell Apoptosis after Renal Ischemia–Reperfusion Injury by Blocking the ATM/P53-Mediated DNA Damage Response

“…Therefore, activation of the DDR signaling pathway may represent a common mechanism that leads to AKI. Studies have confirmed that HMSCs and high-dose vitamin B12 protect renal function after I/R injury by reducing renal superoxide levels and lipid peroxidation, thereby attenuating the DDR and TEC apoptosis [42,43]. After renal I/R injury, application of BA (boric acid) decreased the degree of DNA damage by preventing partially oxidative stress [44].…”

HIF-1α overexpression in mesenchymal stem cell-derived exosome-encapsulated arginine-glycine-aspartate (RGD) hydrogels boost therapeutic efficacy of cardiac repair after myocardial infarction

“…MSCs may serve as therapeutic agents for ischemia-related diseases [ [21] , [22] , [23] , [24] ]. In the present study, human umbilical cord MSCs were used for cell culture and EVs isolation.…”

Molecular Mechanisms of Mesenchymal Stem Cell-Based Therapy in Acute Kidney Injury

“…The binding protein 14-3-3 family could regulate the autophagy process through different signal pathways, such as MAPK, PI3K, and mTOR [ 102 ]. Tseng et al also found that MSCs stimulate the autophagy-related protein expression, such as LC3B, Atg5, and Beclin, in the I/R AKI rat model and then improved AKI recovery [ 78 ]. Yuan et al also identified that hiPSC-derived MSCs secreted the paracrine signal protein, specificity protein (SP1), into recipient TECS, where the SP1 upregulated the sphingosine kinase 1 (SK1) to induce sphinganine-1-phosphate (S1P) formation, which was necessary for the anti-necroptosis effect.…”