Ion channels as a therapeutic target for renal fibrosis

Abstract

Renal ion channel transport and electrolyte disturbances play an important role in the process of functional impairment and fibrosis in the kidney. It is well known that there are limited effective drugs for the treatment of renal fibrosis, and since a large number of ion channels are involved in the renal fibrosis process, understanding the mechanisms of ion channel transport and the complex network of signaling cascades between them is essential to identify potential therapeutic approaches to slow down renal fibrosis. This review summarizes the current work of ion channels in renal fibrosis. We pay close attention to the effect of cystic fibrosis transmembrane conductance regulator (CFTR), transmembrane Member 16A (TMEM16A) and other Cl− channel mediated signaling pathways and ion concentrations on fibrosis, as well as the various complex mechanisms for the action of Ca2+ handling channels including Ca2+-release-activated Ca2+ channel (CRAC), purinergic receptor, and transient receptor potential (TRP) channels. Furthermore, we also focus on the contribution of Na+ transport such as epithelial sodium channel (ENaC), Na+, K+-ATPase, Na+-H+ exchangers, and K+ channels like Ca2+-activated K+ channels, voltage-dependent K+ channel, ATP-sensitive K+ channels on renal fibrosis. Proposed potential therapeutic approaches through further dissection of these mechanisms may provide new therapeutic opportunities to reduce the burden of chronic kidney disease.

Recovery of Water Homeostasis in Adenine-Induced Kidney Disease Is Mediated by Increased AQP2 Membrane Targeting

“…Previous studies have shown that dysregulation of water and electrolyte transport in the kidney contributes to the progression of fibrosis and inflammation. For example, disrupted sodium transport can lead to tubular injury and activation of pro-inflammatory pathways as well as renal fibrosis [ 30 ]. As previously discussed, AQP1 plays a critical role in both tubular injury and the subsequent healing process [ 28 ].…”

Large conductance voltage-and calcium-activated K+ (BK) channel in health and disease

“…Localizing β subunits within specific cells provides valuable insights into the function of BK in these cells (Tricarico et al, 1997). The BK channel in the renal connecting tubule expresses the β2 subunit and deleting this subunit in mice has resulted in high renal potassium retention and hyperkalemia (Yan et al, 2022). Additionally, β4 KO have resulted in low potassium excretion, mild hypertension, and mild fluid retention in mice treated with a high-potassium diet (Grimm et al, 2009).…”

“…The BK channel is activated indirectly by shear stress in the kidney through coupling to TRPV4 channel activation and their role in Ca 2+ influx in endothelial cells (Reiter et al, 2006). Recent observations have shown that some BK channel activators, such as NS1619 and BMS191011, attenuate renal fibrosis and promote proper kidney function in animal models (Yan et al, 2022).…”

“…Furthermore, BK channels are critical for regulating extracellular potassium in the renal system. There is increasing evidence that BK channel activators may reduce renal fibrosis and improve kidney function (Yan et al, 2022). Additionally, alterations in the expression of auxiliary subunits of the BK channel have been linked to potassium retention and hyperkalemia (Grimm et al, 2009).…”

Cystic fibrosis–related metabolic defects: crosstalk between ion channels and organs

“…Other organ systems that are now areas of research focus include the liver, pancreas, sinuses, intestines, and kidneys, among others ( 9 ). The kidneys are of consequence, as they are heavily enriched in ion channels ( 10 ). Defective ion exchange due to CF dramatically changes the metabolic output of the kidney ( Figure 1 ) and the crosstalk of this with other organ systems ( 11 ).…”