Amiloride, a urokinase-type plasminogen activator receptor (uTPA) inhibitor, reduces proteinurea in podocytes

Xu, Lixia; Chi, Neil; Shi, Wei

doi:10.4238/2015.august.14.15

Cited by 9 publications

(8 citation statements)

References 31 publications

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“…In obese tumor patients treated with amiloride, increased MMP3 protein levels and MMP9 activities were detected in tumor tissues, suggesting that exosome-mediated MMP3 protein transfer and subsequent MMP9 activation may also occur in the human body. However, as a pleiotropic agent [ 36 , 37 ], amiloride likely induces MMP3 protein levels and MMP9 activities via other mechanisms. Therefore, whether exosomes are involved in the upregulation of MMP3 protein levels and MMP9 activities requires further study.…”

Section: Discussionmentioning

confidence: 99%

Adipocyte-derived exosomes promote lung cancer metastasis by increasing MMP9 activity via transferring MMP3 to lung cancer cells

Wang

Guo

et al. 2017

Oncotarget

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Obesity is involved in tumor progression. However, the corresponding mechanisms remain largely unknown. Here, we report that adipocytes increase the invasive ability of tumor cells by producing exosomes with a high level of MMP3. Compared with 3T3-L1 cells, 3T3-L1 adipocytes are enriched in MMP3 protein and can transfer MMP3 to 3LL lung cancer cells. Then, MMP3 activates MMP9 activity in 3LL cells and promotes invasion in vitro and in vivo via MMP9. Furthermore, MMP3 protein levels in lung tumor tissues from obese patients are increased compared with those of non-obese patients. In addition, MMP3 protein levels are positively correlated with MMP9 activity in tumor tissues. Therefore, our results reveal a novel mechanism in the adipocyte-derived exosome-mediated promotion of lung tumor metastasis, which extends our knowledge regarding obesity and tumor progression.

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Section: Discussionmentioning

confidence: 99%

Adipocyte-derived exosomes promote lung cancer metastasis by increasing MMP9 activity via transferring MMP3 to lung cancer cells

Wang

Guo

et al. 2017

Oncotarget

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“…Only amiloride but not its ENaC inhibitor analog – triamterene – was reported in animal studies and human case reports to reduce proteinuria, and to improve glomerulosclerosis [11-15, 18], we designed this crossover study which intended to use triamterene as a control drug. Surprisingly, our results show that triamterene reduced proteinuria similarly to amiloride.…”

Section: Discussionmentioning

confidence: 99%

“…Increased expression of uPAR mRNA and protein in podocytes was detected in several proteinuric animal models and human glomerular disease, suggesting upregulated uPAR levels in podocytes might contribute to enhanced podocyte migration, foot process effacement, and eventually proteinuria formation [25-29]. Amiloride, a potassium-sparing diuretic via its inhibition on ENaC, has been shown to suppress uPAR expression in podocytes, reduce podocyte cell motility, decrease proteinuria, and attenuate glomerulosclerosis in proteinuric animal models [9, 18]. These data suggest that amiloride might be a potential antiproteinuric agent via suppressing uPAR expression in podocytes and maintaining a stable function of the glomerular filtration barrier.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Amiloride on Proteinuria in Patients with Proteinuric Kidney Disease

Shen¹,

Alshehri²,

Desale³

et al. 2021

Am J Nephrol

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Introduction: Proteinuric kidney diseases share an aggressive clinical course of developing end-stage renal disease. However, the treatment is limited. Amiloride, an epithelial sodium channel (ENaC) inhibitor, was reported to reduce proteinuria in animal studies and case reports independent of ENaC inhibition. We hypothesized that amiloride not triamterene (an analog of amiloride) would reduce proteinuria in the patients with proteinuric kidney disease. Methods: Patients with proteinuria >1.0 g/day and estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 on a maximum tolerable dose of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers were randomized to receive amiloride 5 mg twice daily or triamterene 50 mg twice daily for 8 weeks, followed by 4 weeks of washout, and then crossed over to the other drug for 8 weeks. The primary outcome was 24-h urine protein reduction. Secondary outcomes were changes in body weight, blood pressure (BP), serum potassium, and eGFR. Data were analyzed by analysis of variance. Results: A total of 12 patients completed the study. Amiloride reduced 24-h urine protein by 38.7% (p = 0.002) and decreased systolic BP by 12.3 mm Hg (p = 0.04). Interestingly, triamterene reduced 24 h urine protein as well, by 32.8% (p = 0.02). Triamterene lowered eGFR by 9.0 mL/min/1.73 m2 (p = 0.007), but it was reversible. The average weight change was insignificant in both groups (p = 0.40 and 0.34 respectively). Three patients withdrew the study due to hyperkalemia. Conclusions: Both amiloride and triamterene significantly reduced proteinuria in patients with proteinuric kidney disease. The anti-proteinuric effect was additive to renin-angiotensin-aldosterone system (RAAS) blockade, given all patients were on RAAS blockade. Hyperkalemia was a safety concern. Larger trials might be needed to examine the antiproteinuric effects of ENaC inhibitors.

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“…The mechanism behind amiloride protection independent of blood pressure is not well understood. One possibility is that amiloride has shown effects on podocyte stabilization both in vitro and in vivo by reducing urokinase-type plasminogen activator receptor (uPAR) [50,51]. Amiloride also decrease urokinase-type plasminogen activator by a direct effect [52].…”

Section: Role Of Ctgf In Proteinuriamentioning

confidence: 99%

A Novel Mechanism of Renal Microcirculation Regulation: Connecting Tubule-Glomerular Feedback

Romero

Carretero

2019

Curr Hypertens Rep

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Purpose of Review-In this review, we summarized the current knowledge of connecting tubule-glomerular feedback (CTGF), a novel mechanism of renal microcirculation regulation that integrates sodium handling in the connecting tubule (CNT) with kidney hemodynamics.Recent Findings-Connecting tubule-glomerular feedback is a crosstalk communication between the CNT and the afferent arteriole (Af-Art), initiated by sodium chloride through the epithelial sodium channel (ENaC). High sodium in the CNT induces Af-Art vasodilation, increasing glomerular pressure and the glomerular filtration rate and favoring sodium excretion. CTGF antagonized and reset tubuloglomerular feedback and thus increased sodium excretion. CTGF is absent in spontaneous hypertensive rats and is overactivated in Dahl salt-sensitive rats. CTGF is also modulated by angiotensin II and aldosterone.Summary-CTGF is a feedback mechanism that integrates sodium handling in the CNT with glomerular hemodynamics. Lack of CTGF could promote hypertension, and CTGF overactivation may favor glomerular damage and proteinuria. More studies are needed to explore the alterations in renal microcirculation and the role of these alterations in the genesis of hypertension and glomerular damage in animals and humans.

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Amiloride, a urokinase-type plasminogen activator receptor (uTPA) inhibitor, reduces proteinurea in podocytes

Cited by 9 publications

References 31 publications

Adipocyte-derived exosomes promote lung cancer metastasis by increasing MMP9 activity via transferring MMP3 to lung cancer cells

Adipocyte-derived exosomes promote lung cancer metastasis by increasing MMP9 activity via transferring MMP3 to lung cancer cells

The Effect of Amiloride on Proteinuria in Patients with Proteinuric Kidney Disease

A Novel Mechanism of Renal Microcirculation Regulation: Connecting Tubule-Glomerular Feedback

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