eEOC-mediated modulation of endothelial autophagy, senescence, and EnMT in murine diabetic nephropathy

Abstract

Diabetic nephropathy is the most frequent single cause of end-stage renal disease in our society. Microvascular damage is a key event in diabetes-associated organ malfunction. Early endothelial outgrowth cells (eEOCs) act protective in murine acute kidney injury. The aim of the present study was to analyze consequences of eEOC treatment of murine diabetic nephropathy with special attention on endothelial-to-mesenchymal transdifferentiation, autophagy, senescence, and apoptosis. Male C57/Bl6N mice (8-12 wk old) were treated with streptozotocin for 5 consecutive days. Animals were injected with untreated or bone morphogenetic protein (BMP)-5-pretreated syngeneic murine eEOCs on days 2 and 5 after the last streptozotocin administration. Four, eight, and twelve weeks later, animals were analyzed for renal function, proteinuria, interstitial fibrosis, endothelial-to-mesenchymal transition, endothelial autophagy, and senescence. In addition, cultured mature murine endothelial cells were investigated for autophagy, senescence, and apoptosis in the presence of glycated collagen. Diabetes-associated renal dysfunction (4 and 8 wk) and proteinuria (8 wk) were partly preserved by systemic cell treatment. At 8 wk, antiproteinuric effects were even more pronounced after the injection of BMP-5-pretreated cells. The latter also decreased mesenchymal transdifferentiation of the endothelium. At 8 wk, intrarenal endothelial autophagy (BMP-5-treated cells) and senescence (native and BMP-5-treated cells) were reduced. Autophagy and senescence in/of cultured mature endothelial cells were dramatically reduced by eEOC supernatant (native and BMP-5). Endothelial apoptosis decreased after incubation with eEOC medium (native and BMP-5). eEOCs act protective in diabetic nephropathy, and such effects are significantly stimulated by BMP-5. The cells modulate endothelial senescence, autophagy, and apoptosis in a protective manner. Thus, the renal endothelium could serve as a therapeutic target in diabetes-associated kidney dysfunction.

Endothelial-Mesenchymal Transition in Vascular Calcification of Ins2Akita/+ Mice

“…They have been shown to contribute to diabetic cardiomyopathy [29], diabetic nephropathy [30], diabetes-associated kidney fibrosis [31] and diabetic retinopathy [32] through various signal pathways. In the diabetic aorta, EndMTs are part of the calcific vasculopathy.…”

“…Then, pro-osteogenic BMP2, which is induced in the diabetic media [14], may drive these cells into the osteogenic lineage with progressive calcification [34]. BMP regulation of proteases, Sox2 and EndMTs could also be associated with other diabetic complications, such as diabetic nephropathy, in which BMP5 has been associated with the activation of EndMTs [30] and polymorphism of Sox2 has significant gender-specific effects [35]. …”

Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health?

“…An inflammatory response appears to contribute to the demise of type 2 diabetic mice. Infusion of early endothelial outgrowth cells seems to improve senescence, induce autophagy, and ameliorate kidney injury in diabetic mice, and infusion of bone marrow cells from young mice ameliorates senescent changes in the kidney in old mice . Thus, stem cells may play a role in protecting against kidney damage in aging diabetic mice.…”

Disease drivers of aging

“…95 Infusion of early endothelial outgrowth cells seems to improve senescence, induce autophagy, and ameliorate kidney injury in diabetic mice. 96 Infusion of bone marrow cells from young mice ameliorates senescent changes in the kidney in old mice. 97 Whether stem cells aid in ameliorating kidney damage in aging diabetic mice needs to be investigated.…”