Abstract
Bone marrow-derived mesenchymal stem cells (MSCs) have contributed to the improvement of diabetic nephropathy (DN); however, the actual mediator of this effect and its role has not been characterized thoroughly. We investigated the effects of MSC therapy on DN, focusing on the paracrine effect of renal trophic factors, including exosomes secreted by MSCs. MSCs and MSC-conditioned medium (MSC-CM) as renal trophic factors were administered in parallel to high-fat diet (HFD)-induced type 2 diabetic mice and streptozotocin (STZ)-induced insulin-deficient diabetic mice. Both therapies showed approximately equivalent curative effects, as each inhibited the exacerbation of albuminuria. They also suppressed the excessive infiltration of BMDCs into the kidney by regulating the expression of the adhesion molecule ICAM-1. Proinflammatory cytokine expression (e.g., TNF-α) and fibrosis in tubular interstitium were inhibited. TGF-β1 expression was down-regulated and tight junction protein expression (e.g., ZO-1) was maintained, which sequentially suppressed the epithelial-to-mesenchymal transition of tubular epithelial cells (TECs). Exosomes purified from MSC-CM exerted an anti-apoptotic effect and protected tight junction structure in TECs. The increase of glomerular mesangium substrate was inhibited in HFD-diabetic mice. MSC therapy is a promising tool to prevent DN via the paracrine effect of renal trophic factors including exosomes due to its multifactorial action.
Highlights
Therapies for Diabetic nephropathy (DN) have previously been limited to drugs for the improvement of blood pressure or blood glucose
Mesenchymal stem cells (MSCs) therapy inhibited the progression of diabetic renal failure, which was indicated by the inhibition of U-alb/Cr after 4 and 8 weeks of initial treatment in both high-fat diet (HFD)-MSC mice compared with HFD-vehicle mice (Fig. 1b) and STZ-MSC mice compared with STZ-vehicle mice (Fig. 2b)
We investigated whether MSCs could ameliorate DN in HFD- and STZ-induced diabetic models by an anti-inflammatory mechanism through inhibition of the hyperinfiltration of bone marrow-derived cells (BMDCs), an anti-fibrotic action, and protection of tubular epithelial cells (TECs) from degeneration and EMT
Summary
Therapies for DN have previously been limited to drugs for the improvement of blood pressure or blood glucose. MSC therapy for DN is suggested to have a main mechanism of action via the various paracrine effects of trophic factors secreted by MSCs24 This hypothesis is reasonable since the number of MSCs in the kidney after systemic injection is very low in relation to therapeutic efficacy. We investigated several effects of the intravenous administration of MSCs in the kidney of an HFD-induced type 2 diabetes (T2D) murine model and an STZ-injected insulin deficiency murine model as follows: (1) effect of MSC-CM containing exosomes in comparison to MSCs; (2) anti-inflammatory effect by inhibiting the hyperinfiltration of BMDCs; (3) anti-fibrotic action and protection of TECs from EMT; (4) anti-apoptotic effect and maintenance of epithelial barrier function in TECs; and (5) glomerular alterations in the HFD-induced T2D model. Our findings may open new prospects for the development of novel therapeutics for DN
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