Increased levels of transforming growth factor-β in HIV-associated nephropathy

Yamamoto, Tatsuo; Noble, Nancy A.; Miller, Dale; Gold, Leslie I.; Hishida, Akira; Nagase, Mitsumasa; Cohen, Arthur H.; Border, Wayne A.

doi:10.1046/j.1523-1755.1999.00296.x

Cited by 72 publications

(43 citation statements)

References 48 publications

(3 reference statements)

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“…In the kidney, plasmin is known to play a major role in the degradation and turnover of the extracellular matrix and especially the glomerular mesangial matrix. 22 In addition, plasmin has long been hypothesized to be involved in renal stone formation because plasmin and urokinase-type plasminogen activator activities are decreased in stone-forming patients. 23 In that study, van Aswegen and colleagues reported that urate inhibited urokinase/plasmin activities at a pH of 3.9 (in the presence of acetate) but is minimal under alkaline condition (in the absence of acetate).…”

Section: Discussionmentioning

confidence: 99%

Urinary Plasmin Inhibits TRPV5 in Nephrotic-Range Proteinuria

Tudpor

Laínez

Kwakernaak

et al. 2012

Journal of the American Society of Nephrology

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Urinary proteins that leak through the abnormal glomerulus in nephrotic syndrome may affect tubular transport by interacting with membrane transporters on the luminal side of tubular epithelial cells. Patients with nephrotic syndrome can develop nephrocalcinosis, which animal models suggest may develop from impaired transcellular Ca 2+ reabsorption via TRPV5 in the distal convoluted tubule (DCT). In nephrotic-range proteinuria, filtered plasminogen reaches the luminal side of DCT, where it is cleaved into active plasmin by urokinase. In this study, we found that plasmin purified from the urine of patients with nephrotic-range proteinuria inhibits Ca 2+ uptake in TRPV5-expressing human embryonic kidney 293 cells through the activation of protease-activated receptor-1 (PAR-1). Preincubation with a plasmin inhibitor, a PAR-1 antagonist, or a protein kinase C (PKC) inhibitor abolished the effect of plasmin on TRPV5. In addition, ablation of the PKC phosphorylation site S144 rendered TRPV5 resistant to the action of plasmin. Patchclamp experiments showed that a decreased TRPV5 pore size and a reduced open probability accompany the plasmin-mediated reduction in Ca 2+ uptake. Furthermore, high-resolution nuclear magnetic resonance spectroscopy demonstrated specific interactions between calmodulin and residues 133-154 of the N-terminus of TRPV5 for both wild-type and phosphorylated (S144pS) peptides. In summary, PAR-1 activation by plasmin induces PKC-mediated phosphorylation of TRPV5, thereby altering calmodulin-TRPV5 binding, resulting in decreased channel activity. These results indicate that urinary plasmin could contribute to the downstream effects of proteinuria on the tubulointerstitium by negatively modulating TRPV5. 23: 182423: -183423: , 201223: . doi: 10.1681 In the kidney, the fine regulation of Ca 2+ balance occurs through the activity of the epithelial Ca 2+ channel TRPV5. 1 TRPV5 is mostly expressed in the distal convoluted tubule (DCT) and connecting tubule of the nephron, where it constitutes the apical entry mechanism for transcellular Ca 2+ reabsorption. TRPV5 is a constitutively active ion channel that bears unique electrophysiologic characteristics, including calmodulin (CaM) and Ca 2+ -dependent inactivation and high selectivity for Ca 2+ . 2,3 The activity of TRPV5 is tightly controlled at multiple levels by an array of different factors, including parathyroid hormone and the serine protease tissue kallikrein. Both parathyroid hormone and tissue kallikrein initiate the phosphorylation of TRPV5 through the cAMP/protein kinase A (PKA) and phospholipase C (PLC)/ diacylglycerol (DAG)/protein kinase C (PKC) signaling cascades, respectively. 4,5 J Am Soc Nephrol

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Section: Discussionmentioning

confidence: 99%

Urinary Plasmin Inhibits TRPV5 in Nephrotic-Range Proteinuria

Tudpor

Laínez

Kwakernaak

et al. 2012

Journal of the American Society of Nephrology

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“…TMEV-or sham-infected tissue culture supernatants were harvested, 24 hours p.i. We measured TGF-β1 in the supernatants, using an ELISA kit (TGF-β1 Quantikine ® ELISA, R&D System, Inc., Minneapolis, MN) (Wang et al, 2003;Yamamoto et al, 1999).…”

Section: Enzyme-linked Immunosorbent Assay (Elisa)mentioning

confidence: 99%

TGF-β1 suppresses T cell infiltration and VP2 puff B mutation enhances apoptosis in acute polioencephalitis induced by Theiler's virus

Tsunoda

Libbey

Fujinami

2007

Journal of Neuroimmunology

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GDVII and DA strains of Theiler's murine encephalomyelitis virus (TMEV) differ in VP2 puff B. One week after GDVII virus infection, SJL/J mice had large numbers of TUNEL + apoptotic cells with a relative lack of T cell infiltration in the brain. DA viruses with mutation in puff B induced higher levels of apoptosis than wild-type DA virus, but levels of inflammation in brains were similar between DA and DA virus mutants. The difference in inflammation among TMEVs could be due to TGF-β1 expression that was seen only in GDVII virus infection and negatively correlated with CD3 + T cell infiltration.

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“…While PAI-1 is essentially undetectable in normal kidney, its mRNA expression and/or protein are increased in numerous models of glomerulosclerosis and in many human glomerular diseases (21)(22)(23)(24)(25)(26)(27), implicating it in the fibrotic process. PAI-1 strongly binds to the vitronectin (Vn) that is laid down at the site of tissue injury (28), concentrating PAI-1 in the fibrotic matrix where it can initially inhibit degradation of the provisional fibrin clot and later inhibit matrix degradation.…”

Section: Introductionmentioning

confidence: 99%

A mutant, noninhibitory plasminogen activator inhibitor type 1 decreases matrix accumulation in experimental glomerulonephritis

Huang¹,

Haraguchi²,

Lawrence³

et al. 2003

J. Clin. Invest.

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110

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In fibrotic renal disease, elevated TGF-β and angiotensin II lead to increased plasminogen activator inhibitor type 1 (PAI-1). PAI-1 appears to reduce glomerular mesangial matrix turnover by inhibiting plasminogen activators, thereby decreasing plasmin generation and plasmin-mediated matrix degradation. We hypothesized that therapy with a mutant human PAI-1 (PAI-1R) that binds to matrix vitronectin but does not inhibit plasminogen activators, would enhance plasmin generation, increase matrix turnover, and decrease matrix accumulation in experimental glomerulonephritis. Three experimental groups included normal, untreated disease control, and PAI-1R–treated nephritic rats. Plasmin generation by isolated day 3 glomeruli was dramatically decreased by 69%, a decrease that was reversed 43% (P < 0.02) by in vivo PAI-1R treatment. At day 6, animals treated with PAI-1R showed significant reductions in proteinuria (48%, P < 0.02), glomerular staining for periodic acid–Schiff positive material (33%, P < 0.02), collagen I (28%, P < 0.01), collagen III (34%, P < 0.01), fibronectin (48%, P < 0.01), and laminin (41%, P < 0.01), and in collagen I (P < 0.01) and fibronectin mRNA levels (P < 0.02). Treatment did not alter overexpression of TGF-β1 and PAI-1 mRNAs, although TGF-β1 protein was significantly reduced. These observations strongly support our hypothesis that PAI-1R reduces glomerulosclerosis by competing with endogenous PAI-1, restoring plasmin generation, inhibiting inflammatory cell infiltration, decreasing local TGF-β1 concentration, and reducing matrix accumulation

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Increased levels of transforming growth factor-β in HIV-associated nephropathy

Abstract: Our findings suggest that overproduction of TGF-beta is involved in the pathogenesis of HIVAN.

Cited by 72 publications

References 48 publications

Urinary Plasmin Inhibits TRPV5 in Nephrotic-Range Proteinuria

Urinary Plasmin Inhibits TRPV5 in Nephrotic-Range Proteinuria

TGF-β1 suppresses T cell infiltration and VP2 puff B mutation enhances apoptosis in acute polioencephalitis induced by Theiler's virus

A mutant, noninhibitory plasminogen activator inhibitor type 1 decreases matrix accumulation in experimental glomerulonephritis

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