Reactive Oxygen Species in Cystic Kidney Disease

Abstract

Polycystic kidney disease (PKD) is a rare but significant renal condition with major implications for global acute and chronic patient care. Oxidative stress and reactive oxygen species (ROS) can significantly alter its pathophysiology, clinical outcomes, and treatment, contributing to negative outcomes, including hypertension, chronic kidney disease, and kidney failure. Inflammation from ROS and existing cysts propagate the generation and accumulation of ROS, exacerbating kidney injury, pro-fibrotic signaling cascades, and interstitial fibrosis. Early identification and prevention of oxidative stress and ROS can contribute to reduced cystic kidney disease progression and improved longitudinal patient outcomes. Increased research regarding biomarkers, the pathophysiology of oxidative stress, and novel therapeutic interventions alongside the creation of comprehensive guidelines establishing methods of assessment, monitoring, and intervention for oxidative stress in cystic kidney disease patients is imperative to standardize clinical practice and improve patient outcomes. The integration of artificial intelligence (AI), genetic editing, and genome sequencing could further improve the early detection and management of cystic kidney disease and mitigate adverse patient outcomes. In this review, we aim to comprehensively assess the multifactorial role of ROS in cystic kidney disease, analyzing its pathophysiology, clinical outcomes, treatment interventions, clinical trials, animal models, and future directions for patient care.

Keywords: ADPKD (autosomal dominant polycystic kidney disease); cystic kidney disease (CKD); mitochondrial antioxidants; oxidative stress; tolvaptan.

Figure 1

Mutations within the Pkd1 genes play a significant role in the pathogenesis of ADPKD, contributing to cyst formation, issues with DNA damage pathways, and cellular disruptions [7,8]. Oxidative stress contributes to an increase in p68, decreasing Pkd1 gene expression by attaching to the Pkd1 promoter and upregulating the expression of PKD-associated miRNAs, resulting in posttranscriptional cleavage and loss of Pkd1 mRNA [9]. Fibrotic markers and PKD signaling pathways are also upregulated, leading to a rise in cystic renal epithelial cell proliferation and resulting fibrosis in ADPKD kidneys [9].

Figure 2

Cyclic adenosine monophosphate (cAMP) plays a significant role in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) in epithelial cells [12]. The cyst is shown in the tubular cell lining, and the PC1 and PC2 complex regulates calcium levels after primary stimuli sensing at the apical pole [12]. Issues with this complex can contribute to modified intracellular Ca2þ levels, with an increased cAMP concentration linked to a decrease in intracellular calcium levels [10]. This rise in cAMP levels further contributes to protein kinase A(PKA)-mediated phosphorylation of pathway mediators, resulting in issues with flow sensing, tubulogenesis, chloride channel cystic fibrosis transmembrane conductance regulator (CFTR)-driven transepithelial fluid secretion, a rise in water channels, and additional transcriptional regulation of cell proliferation factors [10]. In PKD, defects in cilia disrupt cilia-signaling pathways, including calcium balance, Hedgehog, Wnt/B-catenin, and cyclic adenosine monophosphate (cAMP), contributing to cyst formation [6]. In particular, changes in calcium regulation lead to increased intracellular cAMP and high chloride-rich fluid secretion, resulting in aberrant proliferation, increased growth factors, and cystogenesis [6,10,11]. The superscript “1” is meant to cite Ref. [12].

Figure 3

PKD—polycystic kidney disease, AI—artificial intelligence, CRISPR—clustered regularly interspaced short palindromic repeats, CT—computed tomography, and ADPKD—autosomal dominant polycystic kidney disease [49,50,52,53,54,55].