Blocking Ligand Occupancy of the αVβ3 Integrin Inhibits the Development of Nephropathy in Diabetic Pigs

Maile, Laura A.; Busby, Walker H.; Gollahon, Katherine A.; Flowers, W. L.; Garbacik, Nikol; Garbacik, Stefani R; Stewart, Kara R; Nichols, Timothy C.; Bellinger, Dwight A.; Patel, Amit; Dunbar, P. Rod; Medlin, Matt D.; Clemmons, David R.

doi:10.1210/en.2014-1318

Cited by 47 publications

(45 citation statements)

References 44 publications

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“…12,29 In animal models of diabetic kidney disease, blockade of β 3 integrin with the use of a monoclonal antibody was protective. 12,31,32 In addition to its role in the activation of α V β 3 integrin on podocytes, suPAR may mediate kidney injury through several molecular mechanisms. For example, CD40 autoantibodies have been implicated in modifying the effect of suPAR in focal segmental glomerulosclerosis, 33 whereas levels of acid sphingomyelinase-like phosphodiesterase 3b have been implicated in modulating the effect of suPAR in diabetic nephropathy.…”

Section: Discussionmentioning

confidence: 99%

Soluble Urokinase Receptor and Chronic Kidney Disease

et al. 2015

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BACKGROUND Relatively high plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR) have been associated with focal segmental glomerulosclerosis and poor clinical outcomes in patients with various conditions. It is unknown whether elevated suPAR levels in patients with normal kidney function are associated with future decline in the estimated glomerular filtration rate (eGFR) and with incident chronic kidney disease. METHODS We measured plasma suPAR levels in 3683 persons enrolled in the Emory Cardiovascular Biobank (mean age, 63 years; 65% men; median suPAR level, 3040 pg per milliliter) and determined renal function at enrollment and at subsequent visits in 2292 persons. The relationship between suPAR levels and the eGFR at baseline, the change in the eGFR over time, and the development of chronic kidney disease (eGFR <60 ml per minute per 1.73 m2 of body-surface area) were analyzed with the use of linear mixed models and Cox regression after adjustment for demographic and clinical variables. RESULTS A higher suPAR level at baseline was associated with a greater decline in the eGFR during follow-up; the annual change in the eGFR was −0.9 ml per minute per 1.73 m2 among participants in the lowest quartile of suPAR levels as compared with −4.2 ml per minute per 1.73 m2 among participants in the highest quartile (P<0.001). The 921 participants with a normal eGFR (≥90 ml per minute per 1.73 m2) at baseline had the largest suPAR-related decline in the eGFR. In 1335 participants with a baseline eGFR of at least 60 ml per minute per 1.73 m2, the risk of progression to chronic kidney disease in the highest quartile of suPAR levels was 3.13 times as high (95% confidence interval, 2.11 to 4.65) as that in the lowest quartile. CONCLUSIONS An elevated level of suPAR was independently associated with incident chronic kidney disease and an accelerated decline in the eGFR in the groups studied. (Funded by the Abraham J. and Phyllis Katz Foundation and others.)

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Section: Discussionmentioning

confidence: 99%

Soluble Urokinase Receptor and Chronic Kidney Disease

et al. 2015

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“…Therefore, loss of podocin expression is not an inevitable consequence of integrin signaling in podocytes. Regardless of how αvβ3-integrin is activated by circulating factors, several studies have shown efficacy of αvβ3-integrin antagonists in animal models of proteinuric diseases [5,62,63]. As an aside, we should note here that human TNF is only able to activate the type 2 TNF receptor in mice [64], but that receptor is already thought to play a role in driving kidney disease [65].…”

Section: Discussionmentioning

confidence: 99%

Changes in podocyte TRPC channels evoked by plasma and sera from patients with recurrent FSGS and by putative glomerular permeability factors

Kim

Roshanravan

Dryer

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Primary forms of focal and segmental glomeruloslerosis (FSGS) are driven by circulating factors that cause dysfunction or loss podocytes. Rare genetic forms of FSGS can be caused by mutations in TRPC6, which encodes a Ca2+-permeable cationic channel expressed in mesangial cells and podocytes; and NPHS2, which encodes podocin, a TRPC6-binding protein expressed in podocyte slit diaphragm domains. Here we observed that exposing immortalized mouse podocytes to serum or plasma from recurrent FSGS patients for 24 hr increased the steady-state cell-surface abundance of TRPC6, accompanied by an increase in currents through endogenous TRPC6 channels evoked by a hypoosmotic stretch stimulus. These effects were mimicked by the soluble urokinase receptor (suPAR) and by tumor necrosis factor (TNF), circulating factors implicated in nephrotic syndromes. Most but not all of the recurrent FSGS plasma samples that we examined also caused a loss of podocin over a period of several hours. The loss of podocin was also seen following exposure to suPAR but not TNF. However, TNF increased the effects of suPAR on TRPC6 and podocin, and TNF and suPAR are required for the full effects of one of the recurrent FSGS plasma samples. The actions of FSGS plasma, suPAR and TNF on surface abundance of TRPC6 were blocked by cilengitide, an inhibitor of αvβ3-integrin signaling. These data suggest that primary FSGS is a heterogeneous condition mediated by multiple circulating factors, and support TRPC6 and αvβ3-integrin as potential therapeutic targets.

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“…Furthermore, an α v β 3 integrin antibody has been shown to prevent the development of DN in diabetic pigs (Maile et al. ) and diabetic rats (Maile et al. ).…”

Section: Introductionmentioning

confidence: 99%

An integrin antagonist (MK‐0429) decreases proteinuria and renal fibrosis in the ZSF1 rat diabetic nephropathy model

Zhou

Haimbach

et al. 2017

Pharmacology Res & Perspec

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Multiple integrins have been implicated in modulating renal function. Modulation of integrin function can lead to pathophysiological processes associated with diabetic nephropathy such as alterations in the glomerular filtration barrier and kidney fibrosis. The complexity of these pathophysiological changes implies that multiple integrin subtypes might need to be targeted to ameliorate the progression of renal disease. To address this hypothesis, we investigated the effects of MK‐0429, a compound that was originally developed as an αvβ3 inhibitor for the treatment of osteoporosis, on renal function and fibrosis. We demonstrated that MK‐0429 is an equipotent pan‐inhibitor of multiple av integrins. MK‐0429 dose‐dependently inhibited podocyte motility and also suppressed TGF‐β‐induced fibrosis marker gene expression in kidney fibroblasts. Moreover, in the obese ZSF1 rat model of diabetic nephropathy, chronic treatment with MK‐0429 resulted in significant reduction in proteinuria, kidney fibrosis, and collagen accumulation. In summary, our results suggest that inhibition of multiple integrin subtypes might lead to meaningful impact on proteinuria and renal fibrosis in diabetic nephropathy.

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Blocking Ligand Occupancy of the αVβ3 Integrin Inhibits the Development of Nephropathy in Diabetic Pigs

Cited by 47 publications

References 44 publications

Soluble Urokinase Receptor and Chronic Kidney Disease

Soluble Urokinase Receptor and Chronic Kidney Disease

Changes in podocyte TRPC channels evoked by plasma and sera from patients with recurrent FSGS and by putative glomerular permeability factors

An integrin antagonist (MK‐0429) decreases proteinuria and renal fibrosis in the ZSF1 rat diabetic nephropathy model

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