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Kidney Fibrosis and Oxidative Stress: From Molecular Pathways to New Pharmacological Opportunities
Francesco Patera1, Leonardo Gatticchi2, Barbara Cellini2
1Division of Nephrology, Azienda Ospedaliera di Perugia, 06132 Perugia, Italy.
Abstract:
Kidney fibrosis, diffused into the interstitium, vessels, and glomerulus, is the main pathologic feature associated with loss of renal function and chronic kidney disease (CKD). Fibrosis may be triggered in kidney diseases by different genetic and molecular insults. However, several studies have shown that fibrosis can be linked to oxidative stress and mitochondrial dysfunction in CKD. In this review, we will focus on three pathways that link oxidative stress and kidney fibrosis, namely: (i) hyperglycemia and mitochondrial energy imbalance, (ii) the mineralocorticoid signaling pathway, and (iii) the hypoxia-inducible factor (HIF) pathway. We selected these pathways because they are targeted by available medications capable of reducing kidney fibrosis, such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, non-steroidal mineralocorticoid receptor antagonists (MRAs), and HIF-1alpha-prolyl hydroxylase inhibitors. These drugs have shown a reduction in oxidative stress in the kidney and a reduced collagen deposition across different CKD subtypes. However, there is still a long and winding road to a clear understanding of the anti-fibrotic effects of these compounds in humans, due to the inherent practical and ethical difficulties in obtaining sequential kidney biopsies and the lack of specific fibrosis biomarkers measurable in easily accessible matrices like urine. In this narrative review, we will describe these three pathways, their interconnections, and their link to and activity in oxidative stress and kidney fibrosis.
Insights
Oxidative stress drives kidney fibrosis through three key pathways: hyperglycemia, mineralocorticoid signaling, and hypoxia-inducible factor (HIF). Medications targeting these pathways show promise in reducing fibrosis and oxidative stress in chronic kidney disease (CKD).
Area of Science:
- Nephrology
- Pathology
- Molecular Biology
Background:
- Kidney fibrosis, characterized by interstitial, vascular, and glomerular scarring, is a primary driver of renal function loss in chronic kidney disease (CKD).
- Oxidative stress and mitochondrial dysfunction are increasingly recognized as critical contributors to the development and progression of kidney fibrosis.
- Understanding the molecular pathways linking oxidative stress to fibrosis is crucial for developing effective anti-fibrotic therapies.
Purpose of the Study:
- To review the interconnected pathways linking oxidative stress to kidney fibrosis.
- To explore the roles of hyperglycemia, mineralocorticoid signaling, and the hypoxia-inducible factor (HIF) pathway in promoting kidney fibrosis.
- To discuss the therapeutic potential of drugs targeting these pathways for managing chronic kidney disease (CKD).
Main Methods:
- This narrative review synthesizes current research on the molecular mechanisms underlying kidney fibrosis.
- Focuses on three specific pathways: hyperglycemia/mitochondrial energy imbalance, mineralocorticoid signaling, and HIF signaling.
- Examines the impact of targeted therapies, including SGLT2 inhibitors, MRAs, and HIF-PH inhibitors, on oxidative stress and fibrosis.
Main Results:
- Hyperglycemia disrupts mitochondrial energy balance, contributing to oxidative stress and fibrosis.
- Mineralocorticoid receptor activation exacerbates kidney injury and fibrosis via oxidative stress pathways.
- Hypoxia-inducible factor (HIF) pathway modulation influences cellular responses to hypoxia, impacting fibrosis progression.
- Targeted medications like SGLT2 inhibitors, MRAs, and HIF-PH inhibitors demonstrate potential to reduce kidney oxidative stress and collagen deposition.
Conclusions:
- Three key pathways—hyperglycemia, mineralocorticoid signaling, and HIF—link oxidative stress to kidney fibrosis.
- Available medications targeting these pathways show promise in mitigating kidney fibrosis and oxidative stress in CKD.
- Further research is needed to fully elucidate the anti-fibrotic effects of these compounds in humans due to challenges in biopsy analysis and biomarker identification.
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