Lipotoxicity-induced kidney injury : mechanisms and the prospect of stem cell therapy and gene silencing

Abstract

Lipotoxicity, a hallmark of obesity, has been demonstrated to be an independent risk factor for progression of renal disease in humans. The lack of available pharmaceutical approaches for halting lipotoxicity-induced nephropathy results from limited understanding towards the potential pathophysiologic mechanisms, thus it is critical to gain insight into the molecular mechanisms and develop better treatments for lipotoxicity-induced nephropathy. Inspiringly, human induced pluripotent stem cells-derived mesenchymal stem cells (iPS-MSCs) are emerging as a feasible alternative to bone marrow-derived MSCs (BM-MSCs) for cell-based therapy, although the efficiency and mechanism of MSCs-based therapy on lipotoxicity-induced kidney injury remains incompletely defined. Long intergenic noncoding RNA p21 (lincRNA-p21), a well studied noncoding RNA, is widely regarded to associate with the occurrence and progression of diverse diseases, however, its role in lipotoxicity-induced kidney lesion, remains unknown. Accordingly, this study aims to investigate: (i) the therapeutic effect and mechanism of iPS-MSCs and BM-MSCs in mitigating obesity-related nephropathy; (ii) the molecular role and mechanism of lincRNA-p21 in regulating lipotoxicity-induced tubule cells injury.

Here we firstly showed that palmitic acid (PA) stimulation in vitro or high-fat diet (HFD)-induced obesity in vivo aggravated endoplasmic reticulum (ER) stress, inflammation and apoptosis in cultured tubule cells or obese renal cortex. Intriguingly, iPS-MSCs and BM-MSCs showed equivalent effect on preventing obesity-induced albuminuria and histopathology damage to kidney, partly through ameliorating the above pathologic events. More importantly, hepatocyte growth factor (HGF)/c-Met paracrine pathway within obese renal cortex was augmented by either iPS-MSCs or BM-MSCs infusion, as characterized by enhanced expression of HGF in glomeruli and c-Met in tubule cells respectively. In support of this, co-culture of glomerular endothelial cells (GECs) with either iPS-MSCs or BM-MSCs upregulated HGF secretion in GECs exposed to PA. Moreover, both GECs-secreted endogenous HGF and exogenously supplied recombinant HGF weakened PA-elicited ER stress, inflammation and apoptosis in cultured tubule cells, whereas this beneficial impact was abolished by instruction of neutralizing anti-HGF antibody. The current research for the first time shows that iPS-MSCs alleviate obesity-related nephropathy with equivalent efficacy to BM-MSCs, via a previously unknown paracrine signaling mechanism whereby MSCs infusion evokes HGF/c-Met pathway within obese renal microenvironment. Secondly, our data showed that lincRNA-p21 was coordinately increased in the renal cortex of HFD-induced obese mice, and cultured tubule cells in response to PA. A chemically modified oligonucleotide targeting lincRNA-p21 inhibited ER stress, inflammation and apoptosis in PA-stimulated tubule cells. Mechanistic studies revealed that PA suppressed PI3K/AKT/mTOR/Mdm2 signaling cascade and led to enhanced expression of p53 and its transcriptional activity, which eventually resulted in upregulated lincRNA-p21. These lines of evidence suggest lincRNA-p21 as a potential prognostic biomarker and therapeutic target for obesity-related nephropathy. Overall, findings from our current study demonstrate the translational implications of conducting MSCs-based therapy and targeting lincRNA-p21 for controlling the progression of lipotoxicity-induced kidney injury.