Early upregulation of iNOS mRNA expression and increase in NO metabolites in pressurized renal epithelial cells

Abstract

Broadbelt NV, Stahl PJ, Chen J, Mizrahi M, Lal A, Bozkurt A, Poppas DP, Felsen D. Early upregulation of iNOS mRNA expression and increase in NO metabolites in pressurized renal epithelial cells.

Pressure activates epidermal growth factor receptor leading to the induction of iNOS via NFκB and STAT3 in human proximal tubule cells

“…TGF␤ has been shown to be a negative regulator of iNOS expression; iNOS and NO were increased in the kidney of TGF␤-deficient mice (58). eNOS mRNA expression remained unchanged after obstruction and is consistent with our in vitro data (4). EGFR was apically localized in the 24-h obstructed and contralateral kidneys.…”

“…Similarly, activation of NFB has been shown to occur via the EGF/EGFR pathway (20,22,45). Inhibition of NFB in pressure-stimulated OHNA and HKC-8 cells inhibited iNOS expression (4,43). Using inhibitors specific for EGFR, STAT3, and NFB, we demonstrated their effectiveness in blocking iNOS expression in HKC-8 cells in response to pressure, EGF, or CM.…”

“…EGF stimulation of EGFR induces NFB activation in human cancer and proximal tubule cells (20,22), whereas EGFR-STAT3 interaction in the nucleus leads to transcriptional activation of iNOS (37). We and others recently reported that pressurization of human kidney epithelial cells and ONHA leads to the increased expression of iNOS via an NFB-dependent mechanism (4,43).…”

Differential Effects of NO Inhibition in Renal Epithelial and Endothelial Cells in Mono-Culture vs. Co-Culture Conditions

“…The source of NO in the kidney was originally thought to be exclusively the endothelial cells [1], but several studies indicate that tubular epithelial cells are capable of NO synthesis via both constitutive and inducible isoforms of NOS [3][4][5]. In contrast to many organs iNOS appears to be constitutively expressed in the kidney [6,7]. In humans a relationship between the upregulation of renal iNOS and proximal tubular injury during systemic inflammation has been demonstrated [8].…”

Experimental comparison of protective characteristics of enalapril and trimetazidine in diabetic nephropathy

“…Captopril treatment prevented increase in intrarenal ANG II, and reversed expression of nephrin, TGFbeta1, collagen and fibronectin. 30 Locally increased synthesis of angiotensin II (ANG II) in the kidney has been associated with glomerular hypertrophy and tubulo-interstitial fibrosis observed in chronic kidney failure. This action of ANG II is way to be mediated chiefly with transforming growth factor-beta, which stimulates the synthesis and decreases the degradation of extracellular matrix components, as well as collagen types and fibronectin.…”