Novel avenues for treating diabetic nephropathy: new investigational drugs

Lacava, Viviana; Pellicanò, Vincenzo; Ferrajolo, Carmen; Cernaro, Valeria; Visconti, Luca; Conti, Giovanni; Buemi, Michele; Santoro, Domenico

doi:10.1080/13543784.2017.1293039

Cited by 23 publications

(21 citation statements)

References 140 publications

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“…In addition to angiogenesis, microinflammation plays an important role in the development and progression of DKD [34][35][36][37][38]. Both intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) have been found to be upregulated in DKD; as suggested by their names, these two factors facilitate the adhesion of inflammatory cells and recruit circulating immune cells [39,40].…”

Section: Discussionmentioning

confidence: 99%

Diabetic Nephropathy Can Be Treated with Calcium Dobesilate by Alleviating the Chronic Inflammatory State and Improving Endothelial Cell Function

Zhou¹,

Chen²,

Li³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease. However, no effective treatments for this disease are available. Calcium dobesilate (CaD) is widely used to treat diabetic retinopathy. DKD and retinopathy often co-exist and have similar mechanisms of pathogenesis. The aim of the present study was to elucidate the safety and efficacy of CaD in the treatment of DKD. Methods: In the prospective randomised controlled study, 100 DKD from Type 2 diabetes mellitus (DM) patients with a urinary albumin/ creatinine ratio (ACR) ≥30 mg/g and urinary protein level between 150 mg/24 h and 2 g/24 h with GFR> 90ml/min were enrolled. The patients were randomly divided into the treatment group (500 mg of CaD, administered orally, 3 times per day) and the control group. DKD patients were treated for 3 months. In the case control study, DM patients without proteinuria and healthy individuals were also enrolled. Clinical data and related biochemical parameters were collected. Endothelial function markers (VEGF, ET-1, eNOS, NO) and inflammatory markers (MCP-1, ICAM, PTX3) were detected by ELISA. Results: In the prospective randomised controlled study, the 24 h urinary albumin and 24 h urinary protein levels significantly decreased after three months of treatment with CaD in the patients with DKD, but the cystatin C-based glomerular filtration rate (GFR) remained unchanged. In addition, the levels of inflammatory markers (PTX3, MCP-1, hsCRP, ICAM) and endothelial dysfunction markers (VEGF, ET-1) were significantly reduced compared to pre-treatment levels, NO was signifcantly increased post treatment. In the case control study, we found that PTX3, MCP-1, ICAM, VEGF and ET-1 levels were positively correlated with urinary albumin in DKD patients, while the NO level was negatively correlated. Logistic regression analysis showed that PTX3, NO and HbAlc were influential factors in DKD. After patients with DKD were treated with CaD for three months, the 24 h urinary albumin and 24 h urinary protein levels significantly decreased, but the cystatin C-based glomerular filtration rate (GFR) remained unchanged. In addition, the levels of inflammatory markers (PTX3, MCP-1, hsCRP, ICAM) and endothelial dysfunction markers (VEGF, NO, ET-1) were significantly reduced compared to pre-treatment levels. Conclusion: CaD can be safely and effectively used to treatdiabetic nephropathy.

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Section: Discussionmentioning

confidence: 99%

Diabetic Nephropathy Can Be Treated with Calcium Dobesilate by Alleviating the Chronic Inflammatory State and Improving Endothelial Cell Function

Zhou¹,

Chen²,

Li³

et al. 2018

Cell Physiol Biochem

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“…Current strategies available for slowing-down DKD progression largely failed to achieve stable results in the long term. Alternative or additive approaches for maximizing reno-protection are thus eagerly advocated [4]. It is nowadays well recognized that oxidative stress plays a major role in the genesis and worsening of DKD [5].…”

Section: Introductionmentioning

confidence: 99%

Antioxidant agents for delaying diabetic kidney disease progression: A systematic review and meta-analysis

et al. 2017

Self Cite

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BackgroundOxidative stress is a key player in the genesis and worsening of diabetic kidney disease (DKD). We aimed at collecting all available information on possible benefits of chronic antioxidant supplementations on DKD progression.Study designSystematic review and meta-analysis.PopulationAdults with DKD (either secondary to type 1 or 2 diabetes mellitus)Search strategy and sourcesCochrane CENTRAL, Ovid-MEDLINE and PubMed were searched for randomized controlled trials (RCTs) or quasi-RCTs without language or follow-up restriction.InterventionAny antioxidant supplementation (including but not limited to vitamin A, vitamin C, vitamin E, selenium, zinc, methionine or ubiquinone) alone or in combination.OutcomesPrimary outcome was progression to end-stage kidney disease (ESKD). Secondary outcomes were change in albuminuria, proteinuria, serum creatinine and renal function.ResultsFrom 13519 potentially relevant citations retrieved, 15 articles referring to 14 full studies (4345 participants) met the inclusion criteria. Antioxidant treatment significantly decreased albuminuria as compared to control (8 studies, 327 participants; SMD: -0.47; 95% CI -0.78, -0.16) but had apparently no tangible effects on renal function (GFR) (3 studies, 85 participants; MD -0.12 ml/min/1.73m2; 95% CI -0.06, 0.01). Evidence of benefits on the other outcomes of interest was inconclusive or lacking.LimitationsSmall sample size and limited number of studies. Scarce information available on hard endpoints (ESKD). High heterogeneity among studies with respect to DKD severity, type and duration of antioxidant therapy.ConclusionsIn DKD patients, antioxidants may improve early renal damage. Future studies targeting hard endpoints and with longer follow-up and larger sample size are needed to confirm the usefulness of these agents for retarding DKD progression.

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“…On the basis of recent studies, inhibition of JAK-STAT signaling, including increased expression of the suppressors of cytokine signaling proteins and pharmacologic inhibition of JAK and STAT proteins, establish a new therapeutic target for DN (33). Baricitinib (ClinicalTrials.gov Identifier NCT01683409), a selective JAK1 and JAK2 inhibitor, has been investigated in phase 2 randomized clinical trials in participants with type 2 diabetic nephropathy (34). The study has proven that baricitinib treatment resulted in a reduction in albuminuria after 3 months' treatment (35).…”

Section: Discussionmentioning

confidence: 99%

Renal protective effect of Paeoniflorin by inhibition of JAK2/STAT3 signaling pathway in diabetic mice

Wang

et al. 2018

BST

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Paeoniflorin is the main bioactive components of the root of P.lactiflora Pall., and has been widely used as an anti-inflammation and immunomodulatory agent. However, the effect and mechanisms of Paeoniflorin in diabetic nephropathy (DN) remains to be elucidated. In the present study, streptozotocin (STZ)-induced type 1 diabetic mice model was used to investigate the protective effect of Paeoniflorin and the role of the Janus kinase (JAK) 2/signal transducer (STAT) 3 signaling pathway on DN. After treatment with Paeoniflorin at a dose of 25, 50 and 100 mg/kg once a day for 12 weeks, both the functional and histological damage to diabetic mice kidney had been attenuated significantly. Additionally, these reno-protective effects were associated with alleviating macrophage infiltration and inflammatory factors expression as well as suppression of the JAK2/STAT3 signaling pathway. These data reveal that Paeoniflorin attenuates renal lesions in diabetic mice and these protective effects may be associated with the prevention of macrophage infiltration and inhibition of the JAK2/STAT3 signaling pathway.

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Novel avenues for treating diabetic nephropathy: new investigational drugs

Cited by 23 publications

References 140 publications

Diabetic Nephropathy Can Be Treated with Calcium Dobesilate by Alleviating the Chronic Inflammatory State and Improving Endothelial Cell Function

Diabetic Nephropathy Can Be Treated with Calcium Dobesilate by Alleviating the Chronic Inflammatory State and Improving Endothelial Cell Function

Antioxidant agents for delaying diabetic kidney disease progression: A systematic review and meta-analysis

Renal protective effect of Paeoniflorin by inhibition of JAK2/STAT3 signaling pathway in diabetic mice

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