Advances in Therapeutic Targets for Diabetic Nephropathy

Targeting Fibrosis in DN

The most significant pathophysiological process involved in the development of DN is renal fibrosis. Fibrosis leads to mass accumulation of ECM proteins, like collagen and fibronectin, within the kidneys’ glomeruli and interstitium. Effects are therefore multifaceted and include loss of kidney function, which is because both glomerulosclerosis and tubulointerstitial fibrosis will contribute to loss of kidney function.

In recent years, the methods of targeted approaches aimed at inhibition of fibrosis have grown in importance in the research work of diabetic nephropathy. Among them is the blockade of the Wnt/β-catenin signaling pathway, which is also known to be directly related with the process of fibrogenesis. This pathway’s inhibition reportedly causes a decrease in the deposition of ECM in preclinical models. Other promised approaches lie in the blockers of matrix metalloproteinases, which would inhibit these enzymes for ECM remodeling, capable of slowing the velocity of fibrosis and preserving kidney function.

An important research focus in fibrosis is along the line of mesangial cells that are responsible for producing and regulating the extracellular matrix within the glomerulus. Activated mesangial cells under high glucose levels produced higher levels of fibronectin as well as other extracellular matrix proteins. This process can be inhibited through modulation of key pathways, including the TGF-β/Smad3 axis or the PI3K/Akt pathway, to reduce the occurrence of fibrosis as well as improving renal outcomes in diabetic nephropathy.

SOCE: A Therapeutic Target for Calcium Storage

SOCE plays a crucial role in modulating the important functions of the renal tissue and mesangial cells. Current research has described SOCE as an ECE that contributes to the negative regulation of fibrosis and ECM production. Activation of SOCE was shown to repress the TGF-β/Smad3 pathway, which is heavily implicated in favoring the deposition of ECM. Inhibition of SOCE, on the other hand, led to increased expression of ECM proteins and heightened fibrosis.

Disruption of SOCE could also be a potential approach to reducing the burden of fibrosis in diabetic nephropathy. Thapsigargin, the activator of SOCE, has been demonstrated to inhibit the synthesis of ECM components such as collagen IV and fibronectin in both in vitro and in vivo studies. Thus, altering SOCE might well be one of the potential therapeutic interventions to halt or potentially reverse kidney fibrosis in diabetic nephropathy.

Oxidative Stress Pathway in the Progression of DN

Oxidative stress is the primary element that mediates kidney damage from diabetic neuropathy. Hyperglycemia and the accompanying disturbances in metabolism evoke the excessive production of ROS, and the resulting cascade of actions instigates inappropriate reactions, like inflammation, apoptosis, and fibrosis. Replacing oxidative stress has, therefore, become a very important goal of therapeutic research on DN.

Use of antioxidants may be a promising strategy, as antioxidants would scavenge ROS and thus protect renal cells from oxidative insults. A few antioxidants like NAC and PDTC have provided some therapeutic effects because of their ability to reduce oxidative stress and inhibit protein synthesis in the ECM. All these agents have the origin of ROS generation, like disturbed mitochondrial function and upregulation of the pro-oxidant enzyme NADPH oxidase.

Promising results were obtained with drugs that modulate cellular pathways associated with oxidative stress, such as the nuclear factor erythroid 2-related factor 2 pathway. Activation of Nrf2 increases the expression of antioxidant enzymes and enhances the ability of the kidney to adapt to oxidative stress. Clinical trials of Nrf2 activators are under way in patients with diabetic nephropathy.

Angiotensin II and RAS Blockade Modulation

The renin-angiotensin system (RAS) is central to the regulation of blood pressure and fluid balance. In diabetic nephropathy, its overactivation plays a pivotal role. Angiotensin II is the main effector of RAS and enhances vasoconstriction, sodium retention, and inflammation, which are conducive to DN progression. RAS inhibition via ACE inhibitors and ARBs has been one of the cornerstones of DN therapy for several decades.

Although RAS blockade is a cornerstone in clinical practice, many patients remain at risk for disease progression. This has opened new avenues to consider and investigate novel approaches beyond classic RAS inhibitors, including direct renin inhibition. Indeed, direct renin inhibition using aliskiren shows promise from preclinical studies through to early-phase clinical trials in reducing proteinuria and slowing the rate of progression of DN.

Another potential strategy for treatment against DN is the concomitant blockade of RAS and the endothelin system. These two pathways are recognized factors in the perpetuation of vascular dysfunction and fibrosis in DN. Concomitant blockade of these pathways may prove to be more effective in controlling the factors driving kidney damage in diabetic nephropathy.

Targeting Novel Molecular Pathways

Other than the well-recognized therapeutic targets of DN, new molecular pathways are presently coming into identification. Those may later on present potential sites for intervention. One example of such pathways recently implicated in the pathogenesis of DN is the Notch signaling pathway. In excess is the overactivation of the podocytes toward this pathway, and such overactivation has been to contribute to fibrosis and sclerosis of the glomerulus. Notch signaling pathway inhibitors as potential candidates to develop protective effects against kidney injury are under research.

The JAK/STAT pathway is another emerging therapeutic target in diabetic nephropathy. Its activation leads to inflammatory responses, fibrosis, and apoptosis of the kidney cells. Inhibitors of this pathway, such as baricitinib, have proven to reduce proteinuria and improve kidney function in preclinical models, and human trials have been initiated for their efficacy in patients.

Apart from that, advancements in the study of biomarkers have enhanced the identification of patients at a high risk of developing DN and also guided the development of targeted therapies. Generally, markers like TNF receptors and kidney injury molecule-1 (KIM-1) are being researched to establish the role they play in predicting the advancement of disease and response to treatment that ensures more personalized approaches towards DN management.

Conclusion

Diabetic neuropathy remains a very challenging complication of diabetes, but numerous advances have been made in identifying and targeting the molecular mechanisms driving this disease. Attention to some particular pathways involving inflammation, fibrosis, oxidative stress, and others has led researchers to new therapies that may bring revolution in treatment strategies for DN. Thus, the potential future of DN treatment can be the combination of classical therapies such as RAS blockade and new targeted agents for single molecular pathways to be delivered to patients at risk for kidney failure.

References

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