Diabetic nephropathy: an insight into molecular mechanisms and emerging therapies

ABSTRACT

Introduction: Diabetic kidney disease (DKD) is a major cause of morbidity and mortality in diabetes and is the most common cause of proteinuric and non-proteinuric forms of end-stage renal disease (ESRD). Control of risk factors such as blood glucose and blood pressure is not always achievable or effective. Significant research efforts have attempted to understand the pathophysiology of DKD and develop new therapies.

Areas covered: We review DKD pathophysiology in the context of existing and emerging therapies that affect hemodynamic and metabolic pathways. Renin-angiotensin system (RAS) inhibition has become standard care. Recent evidence for renoprotective activity of SGLT2 inhibitors and GLP-1 agonists is an exciting step forward while endothelin receptor blockade shows promise. Multiple metabolic pathways of DKD have been evaluated with varying success; including mitochondrial function, reactive oxygen species, NADPH oxidase (NOX), transcription factors (NF-B and Nrf2), advanced glycation, protein kinase C (PKC), aldose reductase, JAK-STAT, autophagy, apoptosis-signaling kinase 1 (ASK1), fibrosis and epigenetics.

Expert opinion: There have been major advances in the understanding and treatment of DKD. SGLT2i and GLP-1 agonists have demonstrated renoprotection, with novel therapies under evaluation. Addressing the interaction between hemodynamic and metabolic pathways may help achieve prevention, attenuation or even reversal of DKD.

KEYWORDS:

• Diabetic kidney disease
• diabetic nephropathy
• diabetic complications
• prevention
• therapeutic targets
• renoprotection

Article Highlights

1. Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease and is a significant cause of morbidity and mortality worldwide

2. The pathophysiology of DKD involves an interplay of haemodynamic and metabolic factors, providing many potential targets for novel drug therapies as understanding grows

3. The standard of care for management of DKD for the last two decades has been risk factor control and renin-angiotensin system (RAS) inhibition

4. Recent evidence supports a renoprotective effect of sodium-glucose cotransporter 2 (SGLT2) inhibition and glucagon-like peptide 1 (GLP-1) receptor agonists in addition to their hypoglycemic properties

5. New evidence for the endothelin antagonist atrasentan suggests it may benefit DKD in selected patient groups

6. Oxidative stress, the formation of advanced glycation end-products (AGE), cellular signaling and renewal processes, fibrosis and epigenetic regulatory processes are key aspects of the pathophysiology of DKD and potential targets for future drug therapy

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.