Abstract
Lipotoxicity has been implicated in the pathogenesis of obesity-related kidney damage and propagates chronic kidney injury like diabetic kidney disease; however, the underlying mechanisms have not yet been fully elucidated. To date, reduction of lipid acquisition and enhancement of lipid metabolism are the major, albeit non-specific, approaches to improve lipotoxic kidney damage. In the kidneys of high-fat diet (HFD)-fed mice and tubule cells cultured with palmitic acid (PA), we observed a dramatic upregulation of the long intergenic non-coding RNA-p21 (LincRNA-p21) through a p53-dependent mechanism. Kidney tubule cell-specific deletion of LincRNA-p21 attenuated oxidative stress, inflammation, apoptosis, and endoplasmic reticulum stress, leading to reduction of histological and functional kidney injury despite persistent obesity and hyperlipidemia. Mechanistically, HFD- or PA-initiated lipotoxicity suppressed the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR)/murine double minute 2 homolog (MDM2) signaling cascade to activate p53 and enhance the transcriptional activity of LincRNA-p21. Collectively, our findings suggest that the p53/LincRNA-p21 axis is the downstream effector in lipotoxic kidney injury and that targeting this axis particularly in the kidney tubule could be a novel therapeutic strategy.
Highlights
Obesity has been considered as a major risk factor for the development of chronic kidney disease, independent of its association with hypertension, diabetes, and dyslipidemia.[1]
We show for the first time that lipotoxicity-induced kidney lesions were suppressed by deletion of LincRNA-p21 in both cell culture and mouse models of diet-induced obesity (DIO)
Our findings provide convincing evidence that LincRNA-p21 deficiency in kidney tubule cells protects the kidney from multiple high-fat diet (HFD)-induced pathological responses, Figure 3
Summary
Obesity has been considered as a major risk factor for the development of chronic kidney disease, independent of its association with hypertension, diabetes, and dyslipidemia.[1]. During high-fat diet (HFD) feeding, the influx of free fatty acids results in the accumulation of triglycerides in other non-adipose tissues, termed lipotoxicity, and this induces oxidative stress, inflammation, apoptosis, endoplasmic reticulum (ER) stress, and insulin resistance, leading to pathological and functional aberrations in multiple organs, including the kidney.[2]. In addition to the well-known role of tumor protein 53 (p53) in tumor suppression, a plethora of evidence suggests the extensive involvement of p53 in the regulation of energy metabolism and numerous metabolic processes like aging, obesity, and diabetes[3] by manipulation of cell metabolism, energy homeostasis, and cell fate. In HFD-treated animals, p53 was functionally elevated in various tissues accompanied with aggravated chronic inflammation, senescence, and systemic insulin resistance.[3,4] Pharmacologic inhibition or genetic ablation of p53 in mice fed with HFD impeded excess fat accumulation, weight gain, hepatosteatosis, and insulin resistance.[3,5] How p53 activates lipid metabolism in response to HFD treatment is not fully understood and it will be imperative to dissect the tissue- and cell-specific actions of p53 and its downstream signaling pathways in order to unravel a new paradigm of therapy for the chronic inflammatory state in obesity
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