Antiproteinuric effect of DPP-IV inhibitors in diabetic and non-diabetic kidney diseases

Nicotera, Ramona; Casarella, Alessandro; Longhitano, Elisa; Bolignano, Davide; Andreucci, Michele; Sarro, Giovambattista De; Cernaro, Valeria; Russo, Emilio; Coppolino, Giuseppe

doi:10.1016/j.phrs.2020.105019

Cited by 14 publications

(13 citation statements)

References 74 publications

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“…DKD is a complex disease that associates multiple proteins or pathways in its development and progression. DPP4 inhibitors, an emerging drug for diabetes treatment, have been found to exhibit renoprotective effects in addition to glucose-lowering effects ( Hasan and Hocher, 2017 ; Nicotera et al, 2020 ). In the present study, the active ingredient of LCH was potentially found to treat DKD by inhibiting DPP4.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of Podocytes DPP4 Activity Is a Potential Mechanism of Lobeliae Chinensis Herba in Treating Diabetic Kidney Disease

et al. 2021

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Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and has become a serious public health problem worldwide. Dipeptidyl peptidase-4 (DPP4) inhibitors, an emerging drug for the treatment of diabetes, have been found to have renoprotective effects in addition to glucose-lowering effects and therefore have the potential to be a treatment modality for DKD. Lobeliae Chinensis Herba (LCH), a traditional Chinese herb widely used in the treatment of diabetes, has recently been found to have a hypoglycaemic mechanism related to the inhibition of DPP4. Firstly, analysis of single-cell sequencing data from mouse kidneys in the National Center for Biotechnology Information (NCBI) database revealed that DPP4 was specifically upregulated in DKD podocytes and was associated with podocyte proliferation. Subsequently, the network pharmacology approach was applied to the screening of compounds. Twelve LCH active ingredients targeting DPP4 were extracted from the Traditional Chinese Medicine System Pharmacology (TCMSP) database. In addition, these 12 compounds and DPP4 were molecularly docked to predict the probability of them affecting DPP4 activity. In vitro, Quercetin, Methyl rosmarinate, Kaempferol, Diosmetin and Acacetin were demonstrated to retard podocyte proliferation by inhibiting DPP4 activity and were the top five compounds predicted by molecular docking to be the most likely to affect DPP4 activity. The half maximal inhibitory concentration (IC50) of the five compounds for DPP4 activity were as follows. Acacetin Log IC50 = −8.349, 95%CI (−9.266, −7.265), Diosmtrin Log IC50 = −8.419, 95%CI (−8.889, −7.950), Log IC50 = −8.349, 95%CI (−9.266, −7.265), Methyl rosmarinate Log IC50 = −8.415, 95%CI (−8.751, −8.085), Kaempferol Log IC50 = −8.297, 95%CI (−9.001, −7.615), Quercetin Log IC50 = −8.864, 95%CI (−9.107, −8.615). Finally, Quercetin, Methyl rosmarinate, Kaempferol, Diosmetin and Acacetin qualified for pharmacokinetic and drug similarity screening and have the potential to be the most promising oral agents for the treatment of DKD.

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Section: Discussionmentioning

confidence: 99%

“…Immortalized human podocyte and mesangial cell lines were used in this study (Lee, 1995;Ni et al, 2012). Immortalized cells were obtained from primary podocytes and mesangial cells by infection with a hybrid Adeno5/SV40 virus.…”

Section: Cell Culturesmentioning

confidence: 99%

Inhibition of Podocytes DPP4 Activity Is a Potential Mechanism of Lobeliae Chinensis Herba in Treating Diabetic Kidney Disease

et al. 2021

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“…Inflammatory signaling pathways and oxidative stress encourage the excretion of renal transforming growth factor (TGF)-beta and the fabrication of extracellular matrix (ECM) via NF-kB activation, which leads to glomerulosclerosis and tubulointerstitial fibrosis [12]. In particular, saxagliptin limits interstitial fibrosis, glomerular hypertrophy, and macrophage infiltration mediated by NF-kBp65 [13]. Epithelial-to-mesenchymal transition (EMT) is encountered as a basis of ECM production from fibroblasts in DKD [12].…”

Section: The Potential Renal Protection Site Of Dpp-4 Inhibitors In Type-2 Diabetes Mellitusmentioning

confidence: 99%

“…Nonetheless, in a recent analysis of the metadata of 36 randomized controlled trials (RCTs) that were double-blind, with DPP-4 inhibitors for a total of 54,664 patients, the result was no outstanding differences in renal failure comparing DPP-4 inhibitors with placebo or other active antidiabetic agents [14]. Based on an initial study that evaluated the potential effects of vildagliptin on LDL heterogeneity and albuminuria among patients with T2DM complicated by nephropathy, the UACR was reduced by 44.6%, despite eGFR remaining unchanged [13]. Another pilot study evaluated linagliptin's anti-inflammatory effects in T2DM patients and evaluated any various markers of stress by oxidation, C-reactive protein (CRP), UACR, eGFR, and urinary liver fatty acid-binding protein (L-FABP) as a tubulointerstitial injury marker [13].…”

Section: The Potential Renal Protection Site Of Dpp-4 Inhibitors In Type-2 Diabetes Mellitusmentioning

confidence: 99%

“…Based on an initial study that evaluated the potential effects of vildagliptin on LDL heterogeneity and albuminuria among patients with T2DM complicated by nephropathy, the UACR was reduced by 44.6%, despite eGFR remaining unchanged [13]. Another pilot study evaluated linagliptin's anti-inflammatory effects in T2DM patients and evaluated any various markers of stress by oxidation, C-reactive protein (CRP), UACR, eGFR, and urinary liver fatty acid-binding protein (L-FABP) as a tubulointerstitial injury marker [13]. A quarter year later, L-FABP and oxidative stress indicators significantly decreased, regardless of HbA1c, while CRP, UACR, and eGFR remained constant [13].…”

Section: The Potential Renal Protection Site Of Dpp-4 Inhibitors In Type-2 Diabetes Mellitusmentioning

confidence: 99%

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The Role of DPP-4 Inhibitors in Type-2 Diabetes Patients with Chronic Kidney Disease

Alqurashi¹,

Alharthi²,

Alshehri³

et al. 2021

Pharmacophore

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The most popular type of diabetes is Type-2 diabetes mellitus (T2DM) accounting for 90-95% of diagnosed diabetes and continues to overgrow worldwide and in the USA. This rapid growth may be attributed to the increased elderly population, prevalence of obesity among adults and children, socioeconomic development, urbanization, unhealthy diets, and poor physical activities. The administration of antidiabetic agents in addition to cardio-renal protection is strongly required. Adequate glycemic control must be achieved with protection against cardiovascular and renal outcomes simultaneously. DPP-4 inhibitors are novel antidiabetic agents that have recently demonstrated protection against macro and macrovascular diabetes complications, particularly cardio-renal protection. To evaluate the efficacy and safety of DPP-4 inhibitors on chronic kidney disease patients. We used the PubMed database and searched for relevant articles on the topic. We used the Mesh word searching system; DPP-4 inhibitors; complications; adverse reactions. Type-2 Diabetes mellitus; Chronic kidney disease. DPP-4 inhibitors have demonstrated promising renal protection in healthy animal studies. Nevertheless, in humans with type-2 diabetes mellitus, the renal impact is still controversial. Several randomized clinical trials support the renoprotection effect of diabetic nephropathy.

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Influence of Dipeptidyl Peptidase-4 (DPP4) on Mesenchymal Stem-Cell (MSC) Biology: Implications for Regenerative Medicine – Review

Torrecillas-Baena

Gálvez-Moreno

Quesada‐Gómez

et al. 2021

Stem Cell Rev and Rep

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Antiproteinuric effect of DPP-IV inhibitors in diabetic and non-diabetic kidney diseases

Cited by 14 publications

References 74 publications

Inhibition of Podocytes DPP4 Activity Is a Potential Mechanism of Lobeliae Chinensis Herba in Treating Diabetic Kidney Disease

Inhibition of Podocytes DPP4 Activity Is a Potential Mechanism of Lobeliae Chinensis Herba in Treating Diabetic Kidney Disease

The Role of DPP-4 Inhibitors in Type-2 Diabetes Patients with Chronic Kidney Disease

Influence of Dipeptidyl Peptidase-4 (DPP4) on Mesenchymal Stem-Cell (MSC) Biology: Implications for Regenerative Medicine – Review

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