A novel U-STAT3-dependent mechanism mediates the deleterious effects of chronic nicotine exposure on renal injury

Abstract

Previous data from our group have demonstrated (Arany I, Grifoni S, Clark JS, Csongradi, Maric C, Juncos LA. Am J Physiol Renal Physiol 301: F125-F133, 2011) that chronic nicotine (NIC) exposure exacerbates acute renal ischemic injury (AKI) in mice that could increase the risk for development and progression of chronic kidney disease (CKD). It has been shown that proximal tubules of the kidney can acquire characteristics that may compromise structural recovery and favor development of inflammation and fibrosis following injury. Chronic NIC exposure can amplify this epithelial process although the mechanism is not identified. Recently, the unphosphorylated form of signal transducer and activator of transcription-3 (U-STAT3) has emerged as a noncanonical mediator of inflammation and fibrosis that may be responsible for the effects of chronic NIC. We found that levels of transforming growth factor β-1 (TGF-β1), α-smooth muscle actin (α-SMA), fibronectin, monocyte chemotactic protein-1 (MCP-1), and expression of U-STAT3 were increased in the ischemic kidneys of NIC-exposed mice. Chronic NIC exposure also increased TGF-β1-dependent F-actin reorganization, vimentin, fibronectin, and α-SMA expression as well as promoter activity of α-SMA and MCP-1 without significant loss of epithelial characteristics (E-cadherin) in cultured renal proximal tubule cells. Importantly, transduction of cells with a U-STAT3 mimetic (Y705F-STAT3) augmented stress fiber formation and also amplified NIC+TGF-β1-induced expression of α-SMA, vimentin, fibronectin, as well as promoter activity of α-SMA and MCP-1. Our results reveal a novel, chronic NIC-exposure-related and U-STAT3-dependent mechanism as mediator of a sustained transcription of genes that are linked to remodeling and inflammation in the kidney during injury. This process may facilitate progression of AKI to CKD. The obtained data may lead to devising therapeutic methods to specifically enhance the protective and/or inhibit adverse effects of STAT3 in the kidney.

Hypoxia: The Force that Drives Chronic Kidney Disease

“…In addition, the reactive oxygen species produced in response to nicotine also induces mesangial cell proliferation and extracellular matrix deposition through pathways that involve increased expression of cyclooxygenase 2-derived prostaglandins and increased phosphorylation of extracellular signal-regulated protein kinases 1 and 2, c-Jun N-terminal kinases, activator protein 1, and protein kinase B. 195,196,204,[206][207][208][209][210] This aberrant proliferation and deposition mirrors the protein kinase C dependent processes by which hyperglycemia constricts glomerular arterioles to limit blood flow and, hence, oxygen delivery to the kidney. In an additional mirror of hyperglycemia, nicotine also promotes hypoxia by facilitating oxygen-consuming inflammation.…”

“…This occurs through increased expression of unphosphorylated signal transducer and activator of transcription 3 that induces renal proximal tubule cells to secrete the pro-inflammatory cytokine transforming growth factor β1 and the proinflammatory chemokine monocyte chemotactic protein 1. 210 Finally, with a higher daily number of cigarettes smoked or a longer duration of smoking the risk of developing hypertension increases. [211][212][213] Consequently, it is logical to assume that beyond its own specific mechanisms of inducing hypoxiamediated CDK, cigarette smoking also utilizes those manifest in hypertension.…”

Smoking and interstitial lung diseases

“…An in vivo study, by ROOMANS et al [28], reported that nicotine alters the homeostasis of epithelial cells in the lung, enhances inflammatory reactions and increases eosinophil numbers in the trachea. In the mouse kidney, nicotine increases the production of TGF-β and the expression of epithelial-mesenchymal transition markers [29]. While in human hepatic cells it also induces TGF-β and collagen expression, promoting fibrogenesis [30].…”

Maternal nicotine exposure during gestation and lactation induces kidney injury and fibrosis in rat offspring

“…Nicotine has toxic effects in the mesangial cells and proximal tubules of the kidney and causes renal damage (9,10). Nicotine also stimulates expression of markers of epithelialmesenchymal transition, such as vimentin, fibronectin, and α-smooth muscle actin in the renal epithelium (9,10).…”

“…Nicotine also stimulates expression of markers of epithelialmesenchymal transition, such as vimentin, fibronectin, and α-smooth muscle actin in the renal epithelium (9,10). Because nicotine easily crosses the placenta, entering fetal blood, and is distributed in breast milk, the fetal and neonatal rats would be expected to receive nicotine via the placenta and mother's milk (11,12).…”