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Engaging Novel Cell Types, Protein Targets and Efficacy Biomarkers in the Treatment of Diabetic Nephropathy

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Diabetic nephropathy (DN) is a well-known complication of diabetes and leading cause of chronic renal failure and ESRD. Currently, ACEs and ARBs are the standard of care for this disease although trials targeting the renin-angiotensin-aldosterone system (RAAS) demonstrate that they delay the progression to ...

Diabetic nephropathy (DN) is a well-known complication of diabetes and leading cause of chronic renal failure and ESRD. Currently, ACEs and ARBs are the standard of care for this disease although trials targeting the renin-angiotensin-aldosterone system (RAAS) demonstrate that they delay the progression to ESRD to only a limited extent (~18% relative risk reduction). Furthermore dual-targeting of this pathway is less than promising, if not deleterious, as evidenced by the failure of the recent ALTITUDE trial with aliskiren, where in combination with losartan, reduced albuminuria but failed to to impact GFR indicating the need for a better surrogate of renal function in DN. Thus, limited efficacy coupled with our incomplete understanding of this multifaceted disease highlights the importance of unraveling novel targets based on a greater understanding of the pathogenesis of renal impairment in diabetes. We must look beyond ACEs/ARBs and capitalize on blending new technologies, target-disease associations, physiology-based insight, and our ability to mine vast quantities of literature as a means to identify and deliver novel drug candidates into the clinic.

But, how do we identify novel targets within the milieu of scientific publications in cellular and animal models of uncertain predictivity? How do we avoid taking the same path of Bardoxolone, Sulodexide, and Perfenidone that were shown to be efficacious in preclinical animal models yet deemed a failure in patients? Where is the research taking us today and what targets are within reach?

Various signaling pathways involving inflammation, fibrosis, and oxidative stress are implicated in the pathogenesis of DN and the key remains to identify druggable targets within this myriad of cellular events. Moreover, novel therapies may be identified from targeting heretofore unexplored cell types, perhaps the kidney pericyte, deemed by some the ‘neglected cells’ of the kidney that play a vital role renal development, homeostasis, injury, and repair. Or, should we look more closely to podocyte-selective targets central to the regulation of glomerular filtration or can a population of inflammatory cells be targeted to slow disease progression?

Alternatively, do we set our sights within the complicated environment of the renal microvasculature? While early DN may represent an overtly angiogenic environment advanced disease surely represents a condition of capillary loss and excess anti-angiogenic activity. If so, can we reasonably target the renal microvasculature in a manner expected to yield benefit across various stages of DN or might this type of therapy treat only a smaller subset of the DN population?

While a number of specific pathways are under investigation (TGF-, RAAS, PKC) for the treatment of DN, there is a need to look beyond the current targets/pathways and identify novel strategies to improve clinical outcomes. In this Research Topic we will discuss novel cell types and targets that may pave the way to discovering candidate molecules to treat our DN patients. We encourage original research as well as diligent reviews, insightful commentary/perspectives, and novel hypothesis. In this challenging field we also call on authors to pair with others in the field with a different perspective for Point/Counter-Point discussions.


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