Kidney Fibrosis and Oxidative Stress: From Molecular Pathways to New Pharmacological Opportunities

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.

Comparative efficacy and safety of SGLT2is and ns-MRAs in patients with diabetic kidney disease: a systematic review and network meta-analysis

“…Patients with T2D are exposed to substantial risks of mortality and the probability of developing complications due to unresolved metabolic, cellular, and inflammatory events ( 38 ). Upregulation of the MR has been detected in an assortment of clinical conditions, including hyperglycemia, obesity, insulin resistance, high salt intake, and CKD ( 39 – 43 ). Under pathological conditions, the overactivation of the MR prompts the increase of diverse proinflammatory and profibrotic cytokines (e.g., tumor necrosis factor receptor-α, interleukin-1, fibronectin, and transforming growth factor-α) within the cardiovascular and renal system, ultimately resulting in chronic inflammation and fibrosis ( 6 , 44 ).…”

Role of Uremic Toxins, Oxidative Stress, and Renal Fibrosis in Chronic Kidney Disease

“…Numerous studies, therefore, provide evidence that this drug has both anti-inflammatory and antifibrotic effects, so that tissue remodeling is not as strong and we obtain an antiproliferative effect to both the urinary and cardiovascular systems [ 93 , 94 ]. The use of non-steroidal MRAs, according to studies, plays a key role in reducing fibrosis and sclerosis not only in the glomeruli but also in the vascular endothelium and renal interstitium [ 97 ]. For now, we have to wait for papers and studies raising the topic of how to combine, and whether to combine at all, in patients the non-steroidal MRA—finerenone and the previously described SGLT2 [ 93 ].…”