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

Abstract

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.

Kaempferol attenuated diabetic nephropathy by reducing apoptosis and promoting autophagy through AMPK/mTOR pathways

“…Our data showed decreased expressions of nephrin and WT1, accompanied by foot processes fusion and glomerular basement membrane thickening in the kidneys of db/db mice, which were significantly ameliorated with KPF treatment, showing the protective effect of KPF on podocyte in DN. This finding in our study was consistent with the previous findings by Yuanping Li et al (30), and Xinyu Wang et al (31), which showed the inhibition effect of KPF on podocyte apoptosis under hyperglycemic conditions in vitro. Impaired autophagy mediated imbalance of homeostasis in podocytes, contributing to podocyte dysfunction and further renal injury in DN (32).…”

Traditional Chinese Medicine in Treating Primary Podocytosis: From Fundamental Science to Clinical Research

“…Dipeptidyl peptidase 4 (DDP4) is specifically upregulated in DKD podocytes, which may be related to podocyte proliferation. Through analysis of the TCM Systematic Pharmacology database, it was found that quercetin, methyl rosmarinate, kaempferol, diosgenin, and Acacia may inhibit DPP4 activity and the proliferation of DKD podocytes ( Wang et al, 2021 ). High-dose Tripterygium wilfordii can improve the overexpression of nephrin in adriamycin-treated rats and inhibit abnormal proliferation of podocytes so as to reduce proteinuria and glomerulosclerosis ( Wan et al, 2014 ).…”

Vitisin B, a resveratrol tetramer from Vitis thunbergii var. taiwaniana, ameliorates impaired glucose regulations in nicotinamide/streptozotocin-induced type 2 diabetic mice

“…ex DC.) Wight & Arn., 9 quercetin, diosmetin, methyl rosmarinate, kaempferol, and acacetin from Lobelia chinensis Lour., 10 yam ( Dioscorea alata L. cv. Tainong No.…”