Molecular Mechanistic Pathways Targeted by Natural Compounds in the Prevention and Treatment of Diabetic Kidney Disease

Abstract

Diabetic kidney disease (DKD) is one of the most common complications of diabetes, and its prevalence is still growing rapidly. However, the efficient therapies for this kidney disease are still limited. The pathogenesis of DKD involves glucotoxicity, lipotoxicity, inflammation, oxidative stress, and renal fibrosis. Glucotoxicity and lipotoxicity can cause oxidative stress, which can lead to inflammation and aggravate renal fibrosis. In this review, we have focused on in vitro and in vivo experiments to investigate the mechanistic pathways by which natural compounds exert their effects against the progression of DKD. The accumulated and collected data revealed that some natural compounds could regulate inflammation, oxidative stress, renal fibrosis, and activate autophagy, thereby protecting the kidney. The main pathways targeted by these reviewed compounds include the Nrf2 signaling pathway, NF-κB signaling pathway, TGF-β signaling pathway, NLRP3 inflammasome, autophagy, glycolipid metabolism and ER stress. This review presented an updated overview of the potential benefits of these natural compounds for the prevention and treatment of DKD progression, aimed to provide new potential therapeutic lead compounds and references for the innovative drug development and clinical treatment of DKD.

Mulberry leaf extract and neochlorogenic acid ameliorate glucolipotoxicity-induced diabetic nephropathy in high-fat diet-fed db/db mice

“…These signaling pathways play crucial roles in the development of DN by modulating inflammation, oxidative stress, apoptosis, and fibrosis. 38 Our findings suggest that MLE and nCGA may exert their renoprotective effects by targeting multiple signaling pathways, an approach that is potentially more effective than conventional therapeutic treatments that target a single pathway.…”

MAGI2 ameliorates podocyte apoptosis of diabetic kidney disease through communication with TGF‐β‐Smad3/nephrin pathway

“…The molecular mechanisms underlying the onset and development of DKD are still not fully explored, and many drugs that are effective in animal models have repeatedly failed during clinical application. The pathways known to induce apoptosis in DKD include the TGF‐β, AMPK, ROS, endoplasmic reticulum stress (ERS), mTOR, and Notch signaling pathways 68–71 . Previous studies have reported that under high‐glucose conditions, the TGF‐β signaling pathway is active and can be involved in podocyte apoptosis by mediating the Smad signaling pathway.…”

“…The pathways known to induce apoptosis in DKD include the TGF-β, AMPK, ROS, endoplasmic reticulum stress (ERS), mTOR, and Notch signaling pathways. [68][69][70][71] Previous studies have reported that under high-glucose conditions, the TGF-β signaling pathway is active and can be involved in podocyte apoptosis by mediating the Smad signaling pathway. Das et al 72 found that TGF-β1 selectively upregulated the transcription of Nox4 mRNA by Smad2/3, leading to elevated mitochondrial Nox4 protein levels, oxidative stress, mitochondrial dysfunction, and podocyte apoptosis.…”

Pediatric Diabetic Nephropathy: Novel Insights from microRNAs

“…In the early stages of DN, microalbuminuria (defined as the presence of 30–300 mg a day of albumin in urine) is detected in these patients, while albuminuria (>300 mg/day) appeared during the progression of the disease [ 10 ]. Various pathophysiological mechanisms have been supposed in DN development including hyperglycemia, inflammation, oxidative stress, advanced glycation end products, protein kinase C, and poly(ADP-ribose) polymerase activation [ 11 , 12 , 13 ] ( Figure 1 ). Taken together, these factors are responsible for the morphological impairments occurring at renal site in DN, such as glomerular mesangium hypertrophy, podocytes dysfunction, and extracellular matrix proteins accumulation [ 13 , 14 ].…”

“…Various pathophysiological mechanisms have been supposed in DN development including hyperglycemia, inflammation, oxidative stress, advanced glycation end products, protein kinase C, and poly(ADP-ribose) polymerase activation [ 11 , 12 , 13 ] ( Figure 1 ). Taken together, these factors are responsible for the morphological impairments occurring at renal site in DN, such as glomerular mesangium hypertrophy, podocytes dysfunction, and extracellular matrix proteins accumulation [ 13 , 14 ]. From a molecular perspective, different cellular and inflammatory signaling pathways such as transforming growth factor- β (TGF- β ), Phosphoinositide 3-kinase-protein kinase B (PI3K-Akt), Mitogen-activated protein kinase (MAPK) family including P38, extracellular signal-regulated kinases (ERK), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF- κ B), and c-Jun N-terminal kinases (JNKs) have been implied in DN pathogenesis [ 13 , 15 ].…”