Persistent Proteinuria Up-Regulates Angiotensin II Type 2 Receptor and Induces Apoptosis in Proximal Tubular Cells

Abstract

Apoptosis is implicated in the progressive cell loss and fibrosis both at glomerular and tubulointerstitial level. In this study, we examined the potential mechanisms by which persistent proteinuria (protein-overload model) could induce apoptosis. After uninephrectomy (UNX), Wistar rats received daily injections of 0.5 g of bovine serum albumin (BSA)/100 g body weight or saline. Both at day 8 and day 28, rats receiving BSA had proteinuria and renal lesions characterized by tubular atrophy and/or dilation and mononuclear cell infiltration. In relation to control-UNX rats, renal cortex of nephritic rats showed an increment in AT2 mRNA (reverse transcriptase-polymerase chain reaction) and protein (Western blot) expression. In both groups, AT2 receptor immunostaining was mainly localized in proximal tubular cells. Rats with persistent proteinuria showed a significantly increased number of terminal dUTP nick-end labeling positive apoptotic cells compared with UNX-controls, both in glomeruli and tubulointerstitium. Double staining for apoptosis and AT2 receptor showed that most terminal dUTP nick-end labeling positive cells were found in tubules expressing AT2 receptor. Using an antibody that recognizes the active form caspase-3, we observed an increment in caspase-3 activation in rats receiving BSA with respect to those receiving saline. Rats with persistent proteinuria showed a diminution in the phosphorylation of Bcl-2 with respect to UNX-controls both at day 8 and day 28. By contrast, no changes were observed either in the Bax or in the Bcl-2 protein levels. The administration of BSA to UNX rats induced a diminution in the phosphorylation of ERK with respect to UNX-control at all times studied. The changes observed in ERK activities took place without alterations of ERK1/2 protein levels. In summary, our data suggest that persistent proteinuria causes apoptosis in tubular cells through the activation of AT2 receptor, which can, in turn, inhibit MAP kinase (ERK1/2) activation and Bcl-2 phosphorylation.

NF-κB Mediated IL-6 Production by Renal Epithelial Cells Is Regulated by C-Jun NH2-Terminal Kinase

“…Negative cross-talk between the JNK and ERK pathways has been demonstrated previously, although the functional consequences were not investigated (31). Decreased ERK phosphorylation was associated with increased tubular apoptosis in rats with persistent proteinuria (32), indicating that inhibition of ERK activation may contribute to renal failure. However, albumininduced MCP-1 production in mouse TEC was in part mediated by ERK (33).…”

A Possible Anti-Inflammatory Role of Angiotensin II Type 2 Receptor in Immune-Mediated Glomerulonephritis during Type 1 Receptor Blockade

“…AT 2 R induction in tubular epithelial cells has been reported to occur in most renal injury models. 20,28,35 AT 2 R induction during inflammation is believed to occur as a result of the activity of potential cis-elements such as the CCAAT/enhancer-binding protein (C/EBP) sites, the interferon regulatory factor-I site, and the nuclear factor of activated T cells site in the promoter region of the AT 2 R gene that respond to proinflammatory mediators. 11 In addition, our finding that mRNA levels of AT 2 R in PTCs were further increased by the dual-blockade in the CGP/PD group compared with the PC group in Figure 2c suggests that a native AT 2 R function down-regulates its own expression.…”

“…11 Although tissue remodeling is markedly influenced by AT 2 R expression and signaling, it is still unclear whether stimulation of AT 2 R aggravates or attenuates renal interstitial inflammation and fibrogenesis. 2,[15][16][17][18][19][20] Recently, we demonstrated that feedback activation of AT 2 R in response to AT 1 R blockade had anti-inflammatory and antifibrotic effects on advanced immune-mediated glomerulonephritis in SJL mice. 2 In that study, AT 2 R blockade alone did not influence the native course of interstitial inflammation in the day 56 anti-GBM nephritic kidney via AT 1 R, possibly because of a lack of feedback-mediated increase in Ang II synthesis.…”

Efficiency of late conversion from mycophenolate mofetil to everolimus in kidney graft recipients with posttransplant malignancy

“…Другим механизмом протеинурии на фоне сиролимуса счи-тают снижение способности канальцев реабсорбиро-вать профильтровавшийся белок [83,84]. Последнее, как показано в экспериментальных моделях, обуслов-лено усиленным апоптозом эпителия проксимальных канальцев [85,86]. Учитывая отсутствие данных о повышении экспрессии активированных маркеров апоптоза, полагают, что апоптоз, индуцированный сиролимусом, является проявлением прямого токси-ческого действия препарата [87].…”