Abstract
Interstitial fibrosis is a common feature of chronic kidney disease, and platelet-derived growth factor receptor-β (PDGFR-β)-positive mesenchymal cells are reportedly the major source of scar-producing myofibroblasts. We had previously demonstrated that albumin and its derivative R-III (a retinol-binding protein-albumin domain III fusion protein) inhibited the transdifferentiation/activation of hepatic stellate cells (HSCs) to myofibroblasts and that R-III administration reduced liver fibrosis. In this study, we isolated cells (referred to as renal stellate cells, RSCs) from rat kidney tissues using the HSC isolation protocol and compared their morphological and biochemical characteristics with those of HSCs. RSCs shared many characteristics with HSCs, such as storage of vitamin A-containing lipid droplets and expression of HSC markers as well as pericyte markers. RSCs underwent spontaneous transdifferentiation into myofibroblasts in in vitro culture, which was inhibited by albumin expression or R-III treatment. We also evaluated the therapeutic effects of R-III in unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Injected R-III localized predominantly in cytoglobin/stellate cell activation-associated protein (Cygb/STAP)-positive cells in the kidney and reduced renal fibrosis. These findings suggest that RSCs can be recognized as the renal counterparts of HSCs and that RSCs represent an attractive therapeutic target for anti-fibrotic therapy.
Highlights
Chronic kidney disease (CKD) represents a global health burden that affects >10% of adults worldwide, and renal fibrosis, tubulointerstitial fibrosis, is the common final outcome of almost all progressive CKD [1]
We showed that albumin was endogenously expressed in quiescent stellate cells (SCs), but not in activated SCs, and that its forced expression in activated SCs induced a phenotypic reversion of myofibroblasts into early activated cell phenotype, accompanied with the reappearance of cytoplasmic lipid droplets and reduced expression of α-smooth muscle actin (α-SMA)
Similar to hepatic stellate cells (HSCs), which when cultured on plastic undergo spontaneous transdifferentiation/activation in vitro [10], RSCs on day seven after seeding (RSCs d7) and RSCs after passage two (RSCs P2) transformed into myofibroblast-like cells and displayed loss of lipid droplets and increased expression of collagen type I
Summary
Chronic kidney disease (CKD) represents a global health burden that affects >10% of adults worldwide, and renal fibrosis, tubulointerstitial fibrosis, is the common final outcome of almost all progressive CKD [1]. In response to fibrogenic stimuli, quiescent HSCs undergo functional and phenotypic changes, referred to as “activation,” and transdifferentiate into myofibroblast-like cells [10]. This process is characterized by the loss of vitamin A-containing cytoplasmic lipid droplets, increased cellular proliferation, positive staining for alpha-smooth muscle actin (α-SMA), and enhanced synthesis of ECM proteins. In the present study, we investigated whether cells resembling HSCs are present in kidney tissues and determined the therapeutic effects of R-III on unilateral ureteral obstruction (UUO)-induced renal fibrosis
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