Combined AGE inhibition and ACEi decreases the progression of established diabetic nephropathy in B6 db/db mice

Zhao, Feng; Zeng, Yijun; Plati, Anna Rita; Elliot, Sharon J.; Berho, Mariana; Potier, M.; Striker, Liliane J.; Striker, Gary E.

doi:10.1038/sj.ki.5001578

Cited by 66 publications

(54 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This agent is a derivative of vitamin B6 and can reduce serum AGE levels by blocking AGE formation with no effect on the blood levels of glucose or lipids 22.…”

Section: Methodsmentioning

confidence: 99%

Advanced glycation end‐products suppress autophagic flux in podocytes by activating mammalian target of rapamycin and inhibiting nuclear translocation of transcription factor EB

Zhao

Chen

Tan

et al. 2018

The Journal of Pathology

View full text Add to dashboard Cite

Insufficient autophagy in podocytes is related to podocyte injury in diabetic nephropathy (DN). Advanced glycation end‐products (AGEs) are major factors of podocyte injury in DN. However, the role and mechanism of AGEs in autophagic dysfunction remain unknown. We investigated autophagic flux in AGE‐stimulated cultured podocytes using multiple assays: western blotting, reverse transcription–quantitative PCR, immunofluorescence staining, and electron microscopy. We also utilized chloroquine and a fluorescent probe to monitor the formation and turnover of autophagosomes. Mice of the db/db strain were used to model diabetes mellitus (DM) with high levels of AGEs. To mimic DM with normal levels of AGEs as a control, we treated db/db mice with pyridoxamine to block AGE formation. AGEs impaired autophagic flux in the cultured podocytes. Compared with db/db mice with normal AGEs but high glucose levels, db/db mice with high AGEs and high glucose levels exhibited lower autophagic activity. Aberrant autophagic flux was related to hyperactive mammalian target of rapamycin (mTOR), a major suppressor of autophagy. Pharmacologic inhibition of mTOR activity restored impaired autophagy. AGEs inhibited the nuclear translocation and activity of the pro‐autophagic transcription factor EB (TFEB) and thus suppressed transcription of its several autophagic target genes. Conversely, TFEB overexpression prevented AGE‐induced autophagy insufficiency. Attenuating mTOR activity recovered TFEB nuclear translocation under AGE stimulation. Co‐immunoprecipitation assays further demonstrated the interaction between mTOR and TFEB in AGE‐stimulated podocytes and in glomeruli from db/db mice. In conclusion, AGEs play a crucial part in suppressing podocyte autophagy under DM conditions. AGEs inhibited the formation and turnover of autophagosomes in podocytes by activating mTOR and inhibiting the nuclear translocation of TFEB. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

show abstract

“…This agent is a derivative of vitamin B6 and can reduce serum AGE levels by blocking AGE formation with no effect on the blood levels of glucose or lipids 22.…”

Section: Methodsmentioning

confidence: 99%

Advanced glycation end‐products suppress autophagic flux in podocytes by activating mammalian target of rapamycin and inhibiting nuclear translocation of transcription factor EB

Zhao

Chen

Tan

et al. 2018

The Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…10,11 Pyridorin also inhibited formation of advanced glycation and lipoxidation end products and controlled plasma lipids, while limiting the loss of renal function and reducing albuminuria in Zucker rats. 12 Progression of diabetic glomerular histopathologic findings over 15 weeks of therapy decreased in db/db diabetic mice, 13 and improved albuminuria was reported in the KK-A y /Ta mouse model of diabetic nephropathy. 14 Despite the positive preclinical experience, we failed to show that Pyridorin altered the progressive loss of renal function anticipated in our patient population.…”

Section: Discussionmentioning

confidence: 99%

“…Several preclinical studies in rat models of diabetic nephropathy have demonstrated oral Pyridorin to be efficacious in preserving renal function. [10][11][12][13][14] Two small, 24-week clinical safety trials have reported an apparent decrease in the rate of loss of renal function associated with Pyridorin treatment. 15 The purpose of our study was to determine whether 1 year of therapy with Pyridorin delayed the progressive loss of renal function in patients with type 2 diabetes mellitus and advanced nephropathy.…”

mentioning

confidence: 99%

Pyridorin in Type 2 Diabetic Nephropathy

Lewis

Greene

Spitalewiz

et al. 2012

Journal of the American Society of Nephrology

136

View full text Add to dashboard Cite

Pyridoxamine dihydrochloride (Pyridorin, NephroGenex) inhibits formation of advanced glycation end products and scavenges reactive oxygen species and toxic carbonyls, but whether these actions translate into renoprotective effects is unknown. In this double-blind, randomized, placebo-controlled trial, we randomly assigned 317 patients with proteinuric type 2 diabetic nephropathy to twice-daily placebo; Pyridorin, 150 mg twice daily; or Pyridorin, 300 mg twice daily, for 52 weeks. At baseline, the mean age 6 SD was 63.969.5 years, and the mean duration of diabetes was 17.668.5 years; the mean serum creatinine level was 2.260.6 mg/dl, and the mean protein-to-creatinine ratio was 297361932 mg/g. Regarding the primary end point, a statistically significant change in serum creatinine from baseline to 52 weeks was not evident in either Pyridorin group compared with placebo. However, analysis of covariance suggested that the magnitude of the treatment effect differed by baseline renal function. Among patients in the lowest tertile of baseline serum creatinine concentration, treatment with Pyridorin associated with a lower average change in serum creatinine concentration at 52 weeks (0.28, 0.07, and 0.14 mg/dl for placebo, Pyridorin 150 mg, and Pyridorin 300 mg, respectively; P=0.05 for either Pyridorin dose versus placebo); there was no evidence of a significant treatment effect in the middle or upper tertiles. In conclusion, this trial failed to detect an effect of Pyridorin on the progression of serum creatinine at 1 year, although it suggests that patients with less renal impairment might benefit.

show abstract

“…2,3 Most experimental studies of RAS blockade have used chronic nephropathy models resulting from diabetes, 4,5 hypertension, 6,7 nephrotoxicity, 8 reduction of renal mass, 6,9 or chronic renal injury subsequent to acute mesangiolysis induced in rats by anti-Thy-1 antibody 10,11 or subsequent to establishment of an immune complex-induced glomerulonephritis. 12,13 Similarly, the efficacy of RAS blockade in human kidney diseases has been best demonstrated in patients with diabetic nephropathy, 14,15 hypertension, 16,17 or chronic kidney disease (CKD) arising from multiple causes.…”

mentioning

confidence: 99%

Renin-Angiotensin System Blockade Is Renoprotective in Immune Complex–Mediated Glomerulonephritis

Guo

Kowalewska

Wietecha

et al. 2008

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Blockade of the renin-angiotensin system is renoprotective in a variety of chronic nephropathies, but the direct effect of such treatment in active, immune complex-mediated glomerulonephritis is unknown. This study investigated the short-and long-term effects of an angiotensin-converting enzyme inhibitor (enalapril) and an angiotensin II type 1 receptor blocker (losartan) in thymic stromal lymphopoietin transgenic (TSLPtg) mice, which develop mixed cryoglobulinemia and severe cryoglobulinemia-associated membranoproliferative glomerulonephritis. Enalapril and losartan each reduced hypertension, proteinuria, glomerular extracellular matrix deposition, and mesangial cell activation in TSLPtg mice. These renoprotective effects were not observed with hydralazine treatment, despite a similar antihypertensive effect. Treatment with enalapril or losartan also decreased renal plasminogen activator inhibitor-1 in TSLPtg mice, assessed by immunohistochemistry and quantitative real-time reverse transcriptase-PCR. None of the treatments affected immune complex deposition or macrophage infiltration. Overall, enalapril-and losartan-treated TSLPtg mice survived significantly longer than untreated TSLPtg mice. These studies demonstrate that angiotensin blockade may provide renoprotective benefits, independent of its BP-lowering effect, in the treatment of active immune complex-mediated glomerulonephritis. Effective treatment for most forms of glomerulonephritis remains an elusive goal. In cases of immune complex-mediated glomerulonephritis, specific treatment options are often limited to immunosuppressive agents such as glucocorticoids and cytotoxic agents, which have the dual burdens of limited efficacy and multiple severe toxicities. An exception is the case of membranoproliferative glomerulonephritis (MPGN) consequent to cryoglobulinemia associated with longstanding hepatitis C virus (HCV) infection. In that setting, antiviral therapy directed at the underlying HCV infection, typically IFN based, can cause remission of cryoglobulinemia and the MPGN if HCV viremia is eradicated. 1 Unfortunately, this occurs in only a minority of patients with this disorder, and other efficacious therapies either have not been identified or have been tested in only a small number of patients.In recent years, blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II type 1 receptor blockers (ARB) has shown compelling renoprotective effects in chronic renal diseases of humans and animal models. 2,3 Most experimental studies of RAS blockade have used chronic nephropathy models resulting from diabetes, 4,5 hypertension, 6,7 nephrotoxicity, 8 reduction of renal

show abstract

Combined AGE inhibition and ACEi decreases the progression of established diabetic nephropathy in B6 db/db mice

Cited by 66 publications

References 36 publications

Advanced glycation end‐products suppress autophagic flux in podocytes by activating mammalian target of rapamycin and inhibiting nuclear translocation of transcription factor EB

Advanced glycation end‐products suppress autophagic flux in podocytes by activating mammalian target of rapamycin and inhibiting nuclear translocation of transcription factor EB

Pyridorin in Type 2 Diabetic Nephropathy

Renin-Angiotensin System Blockade Is Renoprotective in Immune Complex–Mediated Glomerulonephritis

Contact Info

Product

Resources

About