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.

Keywords: hypoxia-inducible factor; kidney fibrosis; mineralocorticoid signaling; mitochondrial energy imbalance; oxidative stress; sodium-glucose cotransporter 2.

Figure 1

Pathomechanisms driving chronic kidney disease and novel disease-modifying treatment strategies. Hypertension and hyperglycemia are the main causes of CKD, leading to progressive kidney damage, as depicted by the formation of fibrotic tissue. Abnormal activity of RAAS triggers oxidative stress, inflammatory pathways, and fibrinogenesis. Under hyperglycemic conditions, proximal tubule cells have enhanced energy requirements to sustain the incessant reuptake of glucose through the SGLT2 transporters, resulting in altered mitochondrial activity and ROS generation and finally triggering the hypoxia pathway. Many therapeutic strategies under development aim to ameliorate oxidative stress, to dampen the associated inflammatory response, and to slow down the fibrotic tissue deposition with the use of drugs targeting different pathways, such as MR antagonists, GLP-1R agonists, SGLT2 transporter inhibitors, and HIF-PHD inhibitors. Ang II, angiotensin II; CKD, chronic kidney disease; GLP-1R, glucagon-like peptide 1 receptor; GLP-1RA, glucagon-like peptide 1 receptor agonist; HIF-1α, hypoxia-inducible factor 1α; HIF-PHI, HIF-PHD inhibitor; MR, mineralocorticoid receptor; MRAs, mineralocorticoid receptor antagonists. RAAS, renin–angiotensin–aldosterone system; ROS, reactive oxygen species; SGLT2i, sodium glucose transporter 2-inhibitors; TCA, tricarboxylic acid cycle.