Hyaluronan Inhibition as a Therapeutic Target for Diabetic Kidney Disease: What Is Next?

Abstract

Diabetic kidney disease (DKD) is the leading cause of CKD and ESKD in the United States and worldwide. Pharmacotherapy and lifestyle modifications for glycemia, dyslipidemia, and BP control have shown success in slowing the progression of DKD. Traditional treatments, such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and more recently the use of sodium-glucose cotransporter 2 inhibitors, nonsteroidal selective mineralocorticoid receptor antagonists, such as finerenone, and glucagon-like peptide 1 receptor agonists, have led to added benefits on various outcomes. However, significant residual risk for DKD progression remains despite the current standard-of-care approaches. Arteriolar hyalinosis (AH) is among the key findings seen on kidney biopsies of patients with DKD. It results from the excessive accumulation of hyaluronan (HA) in the arterioles. AH has not been targeted specifically by any of the therapeutic methods currently being used. We discuss in this manuscript the potential use of a selective therapy targeting AH and the increased total renal HA deposits using a HA synthesis inhibitor in DKD.

Trial registration: ClinicalTrials.gov NCT00225537 NCT05386420 NCT05295680 NCT05128929 NCT02780752.

Figure 1

Kidney histopathology in diabetic mice. Examples of (A) a normal glomerulus; (B) glomerulus with mesangial expansion, segmental glomerulosclerosis, and a Kimmelstiel-Wilson nodule (arrow); (C) glomerular mesangiolysis; and (D and E) AH. (A and E) Correspond to PAS staining. (B–D) Stained with hematoxylin and eosin. (A) Obtained from 4-MU–treated mice. (B–E) Originated from diabetic animals treated with control diet. Adapted from ref. with permission. PAS, periodic acid–Schiff.

Figure 2

Molecular structure of 4-MU and its metabolites. Adapted from ref. with permission.

Figure 3

Postulated 4-MU mechanism of HA synthesis inhibition. The left scheme shows the normal way HA gets synthesized. The right scheme shows how 4-MU binds to GlcUA instead of UDP so the HAS cannot build HA. HAS, HA-synthase. Adapted from ref. with permission.

Figure 4

Kidney HAs and correlation with plasma glucose and renal function tests. (A) Total and LMW HAs in kidneys from 4-MU–treated (n=5), control (n=5), and heterozygous nondiabetic littermate mice (n=4) at week 18. Values are expressed as HA content per milligram of kidney wet weight. Error bars indicate the median and IQR. Groups were compared using a t test or Mann–Whitney test. (B) Correlation between nonfasting plasma glucose and total kidney HA content at week 18. (C and D) Correlations between total HA (C) or LMW HA content (D) in kidneys and urine ACR at week 17. The y axis values were not available for one control mouse and two heterozygous animals in these analyses. Adapted from ref. with permission. IQR, interquartile range.