Abstract
Diabetic nephropathy (DN) is a leading cause of kidney morbidity. Despite the multilayered complexity of the mechanisms involved in the pathogenesis of DN, the conventional treatment is limited to just a few drug classes fraught with the risk of adverse events, including the progression of renal dysfunction. Phytoceuticals offer a promising alternative as they act on the many-sidedness of DN pathophysiology, multitargeting its intricacies. This paper offers a review of the mechanisms underlying the protective action of these phytoagents, including boosting the antioxidant capabilities, suppression of inflammation, averting the proliferative and sclerosing/fibrosing events. The pathogenesis of DN is viewed as a continuum going from the original offense, high glucose, through the noxious products it generates (advanced glycation end-products, products of oxidative and nitrosative stress) and the signaling chains consequently brought into action, to the harmful mediators of inflammation, sclerosis, and proliferation that eventually lead to DN, despite the countervailing attempts of the protective mechanisms. Special attention was given to the various pathways involved, pointing out the ability of the phytoagents to hinder the deleterious ones (especially those leading to, driven by, or associated with TGF-β activation, SREBP, Smad, MAPK, PKC, NF-κB, NLRP3 inflammasome, and caspase), to promote the protective ones (PPAR-α, PPAR-γ, EP4/Gs/AC/cAMP, Nrf2, AMPK, and SIRT1), and to favorably modulate those with potentially dual effect (PI3K/Akt). Many phytomedicines have emerged as potentially useful out of in vitro and in vivo studies, but the scarcity of human trials seriously undermines their usage in the current clinical practice—an issue that stringently needs to be addressed.
Highlights
In most countries, diabetic nephropathy (DN) is the main cause of chronic kidney disease (CKD) [1]
Diabetic nephropathy (DN) results from the interplay of several distinct but highly interconnected high glucose- (HG-) induced pathways set into motion by aggressive factors, such as oxidative stress [2] and advanced glycation end-products (AGEs), which trigger signaling chains that generate mediators able to instigate reactive processes, including inflammation, cellular proliferation, and interstitial matrix expansion [3]
We considered that a study proved that a herbal product is nephroprotective if it demonstrated lower levels of glomerular injury markers or improved kidney histology or function in the subjects who took the herbal product
Summary
Diabetic nephropathy (DN) ( known as diabetic kidney disease) is the main cause of chronic kidney disease (CKD) [1]. DN results from the interplay of several distinct but highly interconnected high glucose- (HG-) induced pathways set into motion by aggressive factors, such as oxidative stress [2] and advanced glycation end-products (AGEs), which trigger signaling chains that generate mediators able to instigate reactive processes, including inflammation, cellular proliferation, and interstitial matrix expansion [3]. Oxidative stress and inflammation enhance each other, resulting in a vicious circle leading to glomerular sclerosis and interstitial fibrosis [4]. Among the inflammatory mediators involved in DN are nuclear factor kappa-B (NF-κB), monocyte chemotactic protein- (MCP-) 1, and intercellular adhesion molecule(ICAM-) 1. Attracted and activated by MCP-1 and helped by ICAM-1 (promoted by NF-κB), circulating monocytes invade the kidney [5]. Glomerulosclerosis is the hallmark of DN [7] and consists in proteins of extracellular matrix (ECM) (mostly collagen types I, III, and IV and fibronectin [8]) gradually and inexorably encumbering the mesangium, either by lumping together in nodular
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