The Role of Connexin 43 in Renal Disease: Insights from In Vivo Models of Experimental Nephropathy

Abstract

Renal disease is a major public health challenge since its prevalence has continuously increased over the last decades. At the end stage, extrarenal replacement therapy and transplantation remain the only treatments currently available. To understand how the disease progresses, further knowledge of its pathophysiology is needed. For this purpose, experimental models, using mainly rodents, have been developed to unravel the mechanisms involved in the initiation and progression of renal disease, as well as to identify potential targets for therapy. The gap junction protein connexin 43 has recently been identified as a novel player in the development of kidney disease. Its expression has been found to be altered in many types of human renal pathologies, as well as in different animal models, contributing to the activation of inflammatory and fibrotic processes that lead to renal damage. Furthermore, Cx43 genetic, pharmacogenetic, or pharmacological inhibition preserved renal function and structure. This review summarizes the existing advances on the role of this protein in renal diseases, based mainly on different in vivo animal models of acute and chronic renal diseases.

Mesenchymal stromal cells-derived secretome attenuates cisplatin induced injury in vitro modifying the interplay between proximal tubular epithelial cells and macrophages

“…Of note, the concentration of cisplatin used to treat the co-culture system was doubled to 30 µM as it seemed that the coating of the transwell membrane increased ciPTEC tolerance to cisplatin (data not shown). ciPTECs from cultures treated with cisplatin and CM were stained for CX-43, a gap junction protein whose expression has been implicated in various nephropathologies (31). The level of CX-43 expression was elevated by the cisplatin treatment up to 4 ± 3.46-and 3.2 ± 1.32-fold in ciPTEC cultured alone and co-cultured with macrophages, respectively (Fig.…”

Adipose Stromal Cells-Derived Secretome Attenuates Cisplatin-Induced Injury In Vitro Surpassing the Intricate Interplay Between Proximal Tubular Epithelial Cells and Macrophages

“…As ciPTECs were now seeded on inserts, live-cell imaging of apoptosis was not possible, thus immunofluorescence was performed. Next to Apotracker staining and nuclear fragmentation indicative for apoptosis, connexin-43 (CX-43) was analyzed, a gap junction protein implicated in various nephropathologies [31]. Cisplatin treatment increased CX-43 expression levels 4 ± 3.46-and 3.2 ± 1.32-fold in ciPTECs monoculture and co-culture with macrophages, respectively (Figure 6B,C, compared to UT-CTRL).…”

The complexity of nicotinamide adenine dinucleotide (NAD), hypoxic, and aryl hydrocarbon receptor cell signaling in chronic kidney disease

“…This ultrafiltration process consists of a fenestrated endothelium, glomerular basement membrane, and podocytes that function concurrently through cell junction intercellular communication [ 4 ]. Gap junctions are membrane channels that allow for the direct cytoplasmic exchange of ions and low-molecular weight metabolites (< 1 kDa) between adjacent cells [ 5 ]. The gap junction protein connexin 43 is dysregulated in CKD and blocking this molecule is a suggested therapy in treating the disease [ 4 , 5 ].…”

“…Gap junctions are membrane channels that allow for the direct cytoplasmic exchange of ions and low-molecular weight metabolites (< 1 kDa) between adjacent cells [ 5 ]. The gap junction protein connexin 43 is dysregulated in CKD and blocking this molecule is a suggested therapy in treating the disease [ 4 , 5 ]. Connexin 43 is also a hemichannel that mediates equilibrative transport of nicotinamide dinucleotide (NAD) from the cytosol to the extracellular microenvironment [ 6 ], suggesting that connexin 43 is also associated with cellular NAD homeostasis.…”