Abstract
Nephrotoxicity is a major toxic effect in chemotherapy, which constitutes up to 60% of hospitalized acute kidney injury (AKI). Very few treatment options exist to slow the transition from AKI to subsequent chronic kidney diseases (CKD). Here, we demonstrate that galectin-3 (Gal-3), a β-galactoside binding lectin that plays an important role in kidney fibrosis and renal failure, is one of the key factors for renal injury progression. Ectopic overexpression of Gal-3 significantly decreased the viability of HEK293, simultaneously inducing of cell cycle arrest and apoptosis. However, inhibition of Gal-3, mediated by modified citrus pectin (MCP), predominantly antagonized the pro-apoptotic effects. Mice were pre-treated with normal or 1% MCP-supplemented drinking water 1 week before cisplatin injection. Analyses of serum creatinine and renal tissue damage indicated that MCP-treated mice demonstrated increased renal function and attenuated renal fibrosis after cisplatin-induced injury. MCP-treated mice also demonstrated decreased renal fibrosis and apoptosis, as revealed by masson trichrome staining and Western blot analysis of cleaved caspase-3. Additionally, the protective role of Gal-3 inhibition in the kidney injury was shown to be mediated by protein kinase C α (PKC-α), which promoted cell apoptosis and collagen I synthesis in HEK293 cells. These results demonstrated the potential Gal-3 and PKC-α as therapeutic targets for the treatment of AKI and CKD.
Highlights
Acute kidney injury (AKI) and chronic kidney disease (CKD) are critical global health challenges [1]
Two critical mechanisms contribute to renal fibrosis following renal injury: (i) apoptosis of tubular and (ii) dysregulated modeling of tissue that stems from the imbalance between matrix degradation and matrix synthesis [4,5]
Our findings suggest that Gal-3 inhibition, through the regulation of protein kinase C α (PKC-α), which is a major isoform of PKC in kidneys that maintains normal renal function [21], exerts renal protective effects by alleviating kidney tissue apoptosis, and reducing collagen I synthesis
Summary
Acute kidney injury (AKI) and chronic kidney disease (CKD) are critical global health challenges [1]. The incidence of moderate to advanced stages of CKD increased considerably [2]. Clinical management of the diseases is a challenge and very few treatment options exist currently to slow renal fibrosis progression [3]. The transition of AKI to CDK results from uncontrolled expansion of interstitial extracellular matrix (ECM) and nephron loss [4]. Two critical mechanisms contribute to renal fibrosis following renal injury: (i) apoptosis of tubular and (ii) dysregulated modeling of tissue that stems from the imbalance between matrix degradation and matrix synthesis [4,5]. There is an urgent need for strategies to alleviate tubular injury in parallel to reducing interstitial matrix expansion
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