Renal fibrosis as a hallmark of diabetic kidney disease: potential role of targeting transforming growth factor-beta (TGF-β) and related molecules

ABSTRACT

Introduction

Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease (ESRD) worldwide. Currently, there is no effective treatment to completely prevent DKD progression to ESRD. Renal fibrosis and inflammation are the major pathological features of DKD, being pursued as potential therapeutic targets for DKD.

Areas covered

Inflammation and renal fibrosis are involved in the pathogenesis of DKD. Anti-inflammatory drugs have been developed to combat DKD but without efficacy demonstrated. Thus, we have focused on the mechanisms of TGF-β-induced renal fibrosis in DKD, as well as discussing the important molecules influencing the TGF-β signaling pathway and their potential development into new pharmacotherapies, rather than targeting the ligand TGF-β and/or its receptors, such options include Smads, microRNAs, histone deacetylases, connective tissue growth factor, bone morphogenetic protein 7, hepatocyte growth factor, and cell division autoantigen 1.

Expert opinion

TGF-β is a critical driver of renal fibrosis in DKD. Molecules that modulate TGF-β signaling rather than TGF-β itself are potentially superior targets to safely combat DKD. A comprehensive elucidation of the pathogenesis of DKD is important, which requires a better model system and access to clinical samples via collaboration between basic and clinical researchers.

KEYWORDS:

• Diabetic kidney disease
• inflammation
• renal fibrosis
• transforming growth factor-beta

Article highlights

• DKD still progresses to ESRD, and current therapies only slowdown but cannot stop or reverse this process.

• Inflammation and renal fibrosis are key pathological features in DKD.

• Anti-inflammatory drugs have been developed to combat DKD, but they have not yet been demonstrated to be renoprotective.

• TGF-β is a key driver of renal fibrosis in DKD, but targeting it directly is difficult due to its important physiological and immunomodulatory functions.

• Targeting of some molecules linked to the TGF-β pathway which influence the degree of TGF-β signaling is considered to be a potentially safe and efficacious approach to combat DKD.

• New targets, such as CDA1, which regulate TGF-β signaling, have been identified and show potential as future superior drug targets in DKD.

This box summarizes key points contained in the article.

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.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14728222.2022.2133698.

Additional information

Funding

This paper was not funded.