Pentoxifylline Attenuated the Renal Disease Progression in Rats with Remnant Kidney

Abstract

Abstract. Previous studies have reported that pentoxifylline, a phosphodiesterase inhibitor, attenuates experimental mesangial proliferative glomerulonephritis. This study hypothesized that pentoxifylline could also attenuate the renal disease progression in rats with remnant kidney. After 5/6 subtotal nephrectomy, rats developed progressively elevated proteinuria and plasma creatinine, glomerulosclerosis, interstitial inflammation, and fibrosis, all of which were attenuated by 40 to 60% by pentoxifylline. However, the elevated BP was not changed by pentoxifylline. Pentoxifylline reduced the upregulation of monocyte chemoattractant protein-1 gene by 60% in the cortex of remnant kidney, as well as in a dose-dependent manner in the albumin-or angiotensin II-stimulated proximal tubular cells. It also reduced the upregulation of mitogenic and profibrogenic genes by 50%, including platelet-derived growth factor, fibroblast growth factor-2, transforming growth factor-␤ 1 , connective tissue growth factor, and types I and III collagen in the cortex of remnant kidney. Furthermore, pentoxifylline was found to decrease the numbers of interstitial myofibroblasts by 60% in the cortex of remnant kidney and suppress the proliferation of cultured interstitial fibroblasts. It also reduced the angiotensin II-induced or transforming growth factor-␤ 1

Additive Antiproteinuric Effect of Pentoxifylline in Patients with Type 2 Diabetes under Angiotensin II Receptor Blockade

“…In vivo studies have shown beneficial effects of PTF in different models of renal disease, including murine lupus nephritis (55), crescentic glomerulonephritis (56), and mesangial proliferative glomerulonephritis (57). A recent work in rats with a remnant kidney demonstrated the significant effects of PTF in modulating inflammation, cell proliferation, and fibrosis (58). In particular, PTF administration attenuated interstitial inflammation, downregulated monocyte chemoattractant protein-1 gene expression, reduced the expression of mitogenic and profibrogenic genes, and suppressed the proliferation of interstitial fibroblast and glomerular mesangial cells.…”

Pentoxifylline Attenuates Tubulointerstitial Fibrosis by Blocking Smad3/4-Activated Transcription and Profibrogenic Effects of Connective Tissue Growth Factor

“…Pentoxifylline (PTX), a nonselective phosphodiesterase inhibitor, exerts potent inhibitory effects against cell proliferation, inflammation, and ECM accumulation (13)(14)(15)(16)(17)(18). There is increasing evidence that PTX markedly reduces proteinuria in patients with membranous nephropathy or diabetes (19 -21).…”

“…There is increasing evidence that PTX markedly reduces proteinuria in patients with membranous nephropathy or diabetes (19 -21). PTX can downregulate the gene expression of CTGF and collagen in remnant nephropathy or acute Thy 1 glomerulonephritis (14,15). PTX downregulates CTGF despite sustained TGF-␤1 in angiotensin II-stimulated interstitial fibroblasts and mesangial cells (15).…”

“…PTX can downregulate the gene expression of CTGF and collagen in remnant nephropathy or acute Thy 1 glomerulonephritis (14,15). PTX downregulates CTGF despite sustained TGF-␤1 in angiotensin II-stimulated interstitial fibroblasts and mesangial cells (15). Although PTX inhibits TGF-␤1-induced collagen expression in human peritoneal mesothelial cells through modulating mitogen-activated protein kinase (MAPK) (22), the detailed mechanism by which PTX downregulates CTGF in renal cells is unknown.…”

“…Normal rat kidney fibroblasts (NRK-49F) and proximal tubular epithelial cells (NRK-52E) were cultured as stated previously (15). Subconfluent cells were placed in medium with 0.5% FBS (Life Technologies BRL, Rockville, MD) for 24 h before TGF-␤1 or PTX treatment.…”