BACKGROUND: We have previously documented that human mesangial cell (HMC)-derived tumour necrosis factor-alpha (TNF-alpha) is an important mediator involved in the glomerulo-tubular communication in the development of interstitial damage in IgA nephropathy (IgAN). With the strategic position of podocytes, we further examined the function of podocytes in IgAN. METHODS: Podocyte markers were examined in renal tissues by immunofluorescence. In vitro experiments were conducted with podocytes cultured with polymeric IgA (pIgA) or conditioned medium prepared from HMC incubated with pIgA (IgA-HMC conditioned medium). RESULTS: Glomerular immunostaining for nephrin or ezrin was significantly weaker in patients with IgAN. The immunostaining of IgA and nephrin was distinctly separate with no co-localization. In vitro experiments revealed no effect of pIgA on the expression of these podocyte proteins as IgA from IgAN patients did not bind to podocytes. In contrast, IgA conditioned medium prepared from IgAN patients down-regulated the expression of these podocyte proteins as well as other podocyte markers (podocin and synaptopodin) in cultured podocytes. The mRNA expression of nephrin, erzin, podocin but not synaptopodin correlated with the degree of proteinuria and creatinine clearance. The down-regulation was reproducible in podocytes cultured with TNF-alpha or transforming growth factor-beta (TGF-beta) at concentration comparable to that in the IgA-HMC conditioned medium. The expression of these podocyte proteins was restored partially with a neutralizing antibody against TNF-alpha or TGF-beta and fully with combination of both antibodies. CONCLUSION: Our finding suggests podocyte markers are reduced in IgAN. An in vitro study implicates that humoral factors (predominantly TNF-alpha and TGF-beta) released from mesangial cells are likely to alter the glomerular permeability in the event of proteinuria and tubulointerstitial injury in IgAN.
BACKGROUND: We have previously documented that human mesangial cell (HMC)-derived tumour necrosis factor-alpha (TNF-alpha) is an important mediator involved in the glomerulo-tubular communication in the development of interstitial damage in IgA nephropathy (IgAN). With the strategic position of podocytes, we further examined the function of podocytes in IgAN. METHODS: Podocyte markers were examined in renal tissues by immunofluorescence. In vitro experiments were conducted with podocytes cultured with polymeric IgA (pIgA) or conditioned medium prepared from HMC incubated with pIgA (IgA-HMC conditioned medium). RESULTS: Glomerular immunostaining for nephrin or ezrin was significantly weaker in patients with IgAN. The immunostaining of IgA and nephrin was distinctly separate with no co-localization. In vitro experiments revealed no effect of pIgA on the expression of these podocyte proteins as IgA from IgANpatients did not bind to podocytes. In contrast, IgA conditioned medium prepared from IgANpatients down-regulated the expression of these podocyte proteins as well as other podocyte markers (podocin and synaptopodin) in cultured podocytes. The mRNA expression of nephrin, erzin, podocin but not synaptopodin correlated with the degree of proteinuria and creatinine clearance. The down-regulation was reproducible in podocytes cultured with TNF-alpha or transforming growth factor-beta (TGF-beta) at concentration comparable to that in the IgA-HMC conditioned medium. The expression of these podocyte proteins was restored partially with a neutralizing antibody against TNF-alpha or TGF-beta and fully with combination of both antibodies. CONCLUSION: Our finding suggests podocyte markers are reduced in IgAN. An in vitro study implicates that humoral factors (predominantly TNF-alpha and TGF-beta) released from mesangial cells are likely to alter the glomerular permeability in the event of proteinuria and tubulointerstitial injury in IgAN.
Authors: Seetharamaiah Chittiprol; Phylip Chen; Danica Petrovic-Djergovic; Tad Eichler; Richard F Ransom Journal: Am J Physiol Renal Physiol Date: 2011-06-01
Authors: Darren A Yuen; Kim A Connelly; Andrew Advani; Christine Liao; Michael A Kuliszewski; Judy Trogadis; Kerri Thai; Suzanne L Advani; Yuan Zhang; Darren J Kelly; Howard Leong-Poi; Armand Keating; Philip A Marsden; Duncan J Stewart; Richard E Gilbert Journal: PLoS One Date: 2010-03-04 Impact factor: 3.240
Authors: Hitoshi Suzuki; Krzysztof Kiryluk; Jan Novak; Zina Moldoveanu; Andrew B Herr; Matthew B Renfrow; Robert J Wyatt; Francesco Scolari; Jiri Mestecky; Ali G Gharavi; Bruce A Julian Journal: J Am Soc Nephrol Date: 2011-09-23 Impact factor: 10.121
Authors: Patrícia Garcia Rodrigues; Rafael Nazário Bringhenti; Jonathan Frapporti do Nascimento; Gabriel Joelsons; Mariane dos Santos; Sane Pereira; Francisco Veríssimo Veronese Journal: Int J Clin Exp Pathol Date: 2014-04-15