Research progress of TCM monomer in treating diabetic kidney disease based on inflammatory mechanism

HAN Wen-long, QIN Jia-ping, LIN Ke-xin, LIU Qiang

Department of Pharmacology of Hainan Medical University, Haikou 571199, China

Keywords:

ABSTRACT With the increasing morbidity of diabetes mellitus (DM), diabetic kidney disease (DKD)has become the major reason causing chronic kidney disease (CKD) and end-stage renal disease (ESRD) over the world.However, current treating strategy is aiming at blood glucose controlling and renin-angiotensin system (RAS) restricting which can’t effectively preventing the development of DKD.Recent research indicating that low level of inflammatory and activation of immune system play a significant role in occurrence and progression of DKD.Understanding of inflammatory cascade and its mechanism is conducive to discern novel target of DKD and contributing to design new treating strategy based on anti-inflammatory.For the past few years, an increasing number of evidences proved that Tradit Chin Med (TCM) could delay the progression of ESRD on the basis of inflammatory.In this review, we overview the protective effect against DKD-based renal injury of TCM monomer, offering novel ideas in drug discovery and in mechanism-related research.sd

Diabetes mellitus (DM) is a kind of sophisticated, multi-system metabolic-associated disease, which is symbolized by elevation of blood glucose.DM is now telling on over 500 million people around the world with the increasing trend morbidity by years.It is estimated that by 2 045, number of DM patient will be increase to 630 million[1].Furthermore, DM is also superinducing diversified complications causing organ damage, like cardiac, renal, ocular and vascular, which is a grievous public problem[2].

Diabetic kidney disease (DKD), which is the common etiology of end-stage renal disease (ESRD), is mainly occurring in patients with type 2 diabetes mellitus (T2DM).For DM patients, DKD,as diabetic microvascular complications, will further reduce the quality of life.Even the mechanism of DKD is now impenetrable,high glucose level, inflammatory oxidative stress and autophagy are being taken as the major mechanism of DKD occurring and developing.Although the concrete mechanism of DKD is still undetermined, recent research take aiming at

Part of monomers of Tradit Chin Med (TCM) is capable of improve micro-inflammatory of DKD patients by regulating the development of inflammatory.However, systematic argument of TCM treating DKD is still lacking.Therefore, further discussions of TCM treating DKD is more than necessary.In this review, we overviewed the interaction between inflammatory mechanism and DKD as well as research of TCM treating DKD.

1.The effect of inflammatory mechanism on DKD

Local renal inflammatory plays a crucial role in occurrence and development of DKD[3,4].Being differ from traditional inflammatory, local inflammatory in DKD is in a chronic and low level of micro-inflammatory[5].Renal tubulointerstitial inflammatory components, especially in proximal tubule epithelial cells, play a central role in the pathogenesis of DKD.Inflammatory factors and cells, in a multi-targeted and multi-routed way,influence DKD.Renal micro-inflammatory induced DKD fibrosis reaction, including cytokines and fibro-genic factors released by macrophage and other immune cells[6] interacting with renal cells,inducing micro-environments[7], even triggering fibrotic cascade[4].Inflammatory factors, secreted by some cells in the kidney, which mediate chemokines and inflammatory cells to form inflammatory networks, sequentially amplifying and continuing the inflammatory process in the kidney.Therefore, inhibiting the entry of inflammatory factors and inflammatory cells into the kidney will have a certain protective effect on the kidney[8].

1.1 Inflammatory and DKD

During DKD micro-inflammatory, macrophages generate an excess of inflammatory cytokines, such as IL-6, TNF-α, NO, PGE2,iNOS, COX-2, VEGF, inducing cell necrosis and tissue damage.AIF-1 and IGFBP5, factors of regulating inflammatory and immune reaction, also participate in DKD inflammatory.The expression of AIF-1 and IGFBP5 significantly elevate will induce kidney produce inflammatory reaction.Up-regulated inflammatory factor cytokines trigger The up-regulated inflammatory factors will induce the increase of oxygen radical level in the body, weaken the antioxidant capacity, appear oxidative stress damage, and further aggravate inflammation[9].

1.2 Inflammatory cell and DKD

The accumulation of inflammatory cell in kidney, like monocyte,is also closed related to DKD.TNF-α and other proinflammatory factors, locally synthesized and secreted by inflammatory cells, directly damage the structure of kidney, renal epithelialmesenchymal transition (EMT) was induced, triggering accumulation of extracellular matrix (ECM), eventually causing kidney infiltrated by macrophage so that inducing renal inflammatory.

Meanwhile, TNF-α can induce inflammation by chemotaxis monocytes, neutrophils and other inflammatory cells, promoting the phagocytosis of monocytes and macrophages, and further enhance inflammation[10].Moreover, the up-regulation expression of chemokines and adhesion molecules induce can also induce the migration of inflammatory cells to the kidney tissue, participate in the formation of lymphoid tissue and chronic kidney inflammation,and ultimately enhance the inflammatory response and accelerate kidney injury[11].CX3CL1 is expressed by a variety of cells in the kidney under inflammatory conditions, and CX3CL1 can induce leukocyte orientation to the kidney[12].Similar to CCL20[13], the combination of CCL2 and its receptor CCR2 can increase the adhesion and infiltration of monocyte macrophages, induce IL-6 secretion, lead to mesangial cell proliferation and matrix deposition,cause glomerular inflammation and sclerosis and renal interstitial fibrosis[11].

2.Inflammatory signaling pathways and DKD

Participating in activation of signaling pathways, parts of inflammatory mediators, NF-κB pathway, JAK/STAT pathway,Nrf2/HO-1 pathway, MAPK pathway and Wnt pathway, mediate inflammatory response[9].These pathways are jointly regulated by a variety of factors, and meanwhile, mutual transformation of antiinflammatory, anti-autophagy and anti-apoptosis exist in related pathways, such as inflammation is relevant to oxidative stress[3,14-16].

2.1 NF-κB signaling pathway and DKD

The activation of NF-κB pathway is one of the key factors in inducing DKD inflammation.When this pathway is activated,it stimulates downstream signals, enhances the expression of inflammatory factors and cell adhesion proteins, and promotes glomerulosclerosis[17], eventually aggravate renal injury on DKD.

Activation of NF-κB signaling pathway is one of key factors of inducing DKD inflammatory.When this pathway is activated,it stimulates downstream signals, enhances the expression of inflammatory factors and cell adhesion proteins, promotes glomerular sclerosis, and ultimately aggravates the damage of DKD to the kidney[18].Yang et al[19] used NF-κB inhibitors to reduce the infiltration of macrophages in the kidney of diabetic rats, inhibit the production of inflammatory cytokines, reverse renal dysfunction and achieve the effect of kidney protection.

2.2 JAK-STAT signaling pathway and DKD

In the development of DKD, the JAK/STAT pathway is activated by upstream signals such as high concentration of glucose, AGEs and oxidative stress, which induce cytokines to co-participate in inflammation, fibrosis and cell proliferation[20].Studies have shown that autophagy regulation of podocytes is inhibited after JAK-STAT pathway is activated by high glucose concentration.The abnormal regulation of autophagy is one of the pathogeneses of DKD.If the body cannot effectively remove the damaged proteins and organelles, the injury of podocytes and the progression of DKD will be aggravated[21].Excess ROS in oxidative stress also exacerbates inflammatory processes by activating NF-κB, which triggers the JAK-STAT pathway[1,3].Down-regulating the JAK/STAT signaling pathway, reducing the expression of NF-κB and restoring the autophagy of podocytes will have a protective effect on DKD renal function[22].

Fig 1 Interaction between inflammation and DKD

3.Study on prevention and treatment of DKD by TCM monomer based on inflammatory mechanism

Several studies have shown that some Tradit Chin Med monomeric such as baicalin, isoflavone, allicin can inhibit NF-κB pathway,reduce kidney inflammation, reduce the expression of inflammatory factors in renal tubule epithelial cells of DKD mice, reduce albuminuria of DKD mice, and protect kidney tissue[23-25].Some TCM monomers also inhibit the activity of JAK/STAT signaling pathway, reduce the expression of inflammatory factors in kidney[26],promoting the proliferation of renal tubular epithelial cells, and inhibit cell apoptosis[27].

3.1 Tripterygium glycosides and Triptolide

The effective ingredients extracted from Tripterygium wilfordii,such as Triptolide and Ttripterygium glycosides, have strong antiinflammatory effects and have been widely used in the treatment of various glomerular diseases and various autoimmune diseases[28,29].Tripterygium polyglycoside reduces TNF in renal tissue of diabetes TNF-α,IL-6,INF-γ and MCP-1.which reduces the expression of p-JAK2 and p-STAT3 protein, down regulate JAK/STAT signaling pathway, reduce inflammation, and reduce the degree of renal tissue lesions in diabetes rats[30].Triptolide can inhibit NF-κB signaling pathway, reducing the expression of pro-inflammatory factors such as MCP-1 and ICAM-1, exerting anti-inflammatory effects and protecting the kidneys[31,32].

3.2 Paeoniflorin

Total glucosides of paeony are a collective term for various monoterpene compounds, of which paeoniflorin accounts for the largest proportion[33].Paeoniflorin can not only inhibit MCP-1 and TNF- α and IL-1 and other inflammatory factors to prevent necrosis and tissue damage.It can also reduce the expression of p-JAK2 and p-STAT3 protein in renal cells under high glucose, down regulate JAK/STAT signaling pathway, reduce the inhibition of podocyte autophagy, thereby reducing inflammation of renal tissue and protecting the kidney[34,35].

3.3 Astragalus polysaccharide and Astragaloside IV

Astragalus active ingredients are astragaloside IV, Astragalus polysaccharide and so on[27,36].Astragalus polysaccharide can not only regulate JAK-STAT signaling pathway, inhibit the expression of p-STAT1, p-STAT3, -SMA and other proteins in renal tubular epithelial cells, alleviate podocyte apoptosis and reduce the levels of IL-1β and IL-18 and other inflammatory factors[37].It can also improve organ damage caused by insulin resistance.Astragaloside IV can reduce the expression levels of TGF-β1, Smad3, p-Smad2/3 and α-SMA, increase the expression levels of Smad7 and e-cadherin, and inhibit the excessive proliferation of mesangial membrane and renal fibrosis caused by DKD[38].

3.4 Salvianolic acid

Salvianolic acid is a water-soluble phenolic acid compound in Salvia miltiorrhiza[38].Salvianolic acid can regulate the JAK/STAT signaling pathway, reduce the expression levels of JAK2, STAT3 and other proteins in DKD rats, inhibit renal fibrosis and protect the kidney[39].In addition, salvianolic acid can also inhibit TGF-β1/Smad signaling pathway transduction, reduce the apoptosis of DKD renal tissue cells, reduce the protein expression levels of TGF-β1,p-Smad2 and Smad2 in renal tissue, and improve renal fibrosis and inflammation in DKD mice[40].Clinical experiments have shown that salvianolic acid can reduce the levels of TNF-α and IL-6 in diabetic patients, assist in the treatment of diabetic nephropathy, and effectively reduce inflammatory response in patients[41].

Fig 2 Interaction between signal pathway and DKD

3.5 Berberine

Berberine is an alkaloid extracted from Coptidis and cypress[42].By inhibiting the NF-κB pathway, berberine inhibits the inflammation and fibrosis of renal tubule cells, alleviates the inflammatory response and the apoptosis of podocytes induced by high glucose in DKD rats.Meanwhile, TGF-β expression was decreased,ECM deposition was inhibited, and mesangial cell proliferation was inhibited[43].If berberine is combined with NF-κB pathway inhibitor pyrrolidine dithiocarbamate (PDTC), it can better block NF-κB pathway, and strengthen the effect of berberine on inhibiting podocellular inflammation and apoptosis[44].

3.6 Other TCM monomers

Cordyceps militaris polysaccharide can inhibit the expression of JAK/STAT signaling pathway, enhance autophagy, inhibit oxidative stress, and ultimately reduce kidney inflammation[29].Ge et al.sfound that curcumin could reverse the pathological damage of the kidney in DKD rats, reduce the expression levels of TGF-β1 and p-AMPK protein in the kidney, and thus alleviate the renal fibrosis in rats with diabetic nephropathy.Paeonol can reduce inflammation by inhibiting the expression of NLRP3/Caspase-1, reducing the release of inflammatory cytokines[45] Rhein interferes with PI3K/Akt/FoxO1 signaling pathway in the kidney to lower blood sugar and protect the kidney[46].

Tab 1 The anti-inflammatory mechanism of TCM monomers

4.Summary and prospect

For DKD, the body is stimulated by long-term high sugar state and produces inflammatory response.At the same time, this inflammation continuously activates the overproduction of ROS and is damaged by oxidative stress, which in turn further aggravates the inflammatory response.The interaction between oxidative stress and micro-inflammation has a serious impact on DKD.At present,the anti-inflammatory mechanism of Tradit Chin Med has been thoroughly studied at home and abroad.Some Tradit Chin Med and its extracts can improve the inflammatory damage of diabetic kidney tissue and protect the kidney.With the in-depth study on the mechanism of TCM intervention in DKD, the development of new TCM drugs targeting multiple inflammatory pathways for prevention and treatment of DKD will be a promising therapeutic strategy.Actively seeking effective anti-inflammatory and antioxidant TCM treatment methods may be a hot research direction in the next treatment of DKD.

Description of author’s contribution:

Han Wenlong: Participated in the main writing and revision of the article.Qin Jiaping, Lin Kexin: Participated in the collection, sorting and analysis of materials and data.Liu Qiang: Participate in topic selection, conception and design.

Description of conflict of interest:

All authors declare no conflict of interest.