The Role of Esm-1 in Diabetic Kidney Disease: More Than Just a Biomarker

Diabetic kidney disease (DKD), or diabetic nephropathy, is a debilitating disease seen in 40% of patients who have diabetes (1). It is a global epidemic and is the most common cause of CKD and new onset ESKD. DKD is a complex, multifarious disease, with diverse overlapping structural, physiologic, hemodynamic, and inflammatory components, all of which result in a progressive decline in the GFR, an immunocompromised state, and an increased risk of cardiovascular disease. However, despite the significance of this disease process, until recently the standard of care to slow its progression was essentially limited to hyperglycemia control, in conjunction with treatment of hypertension using maximally tolerated angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Although this strategy is effective, the overall prevalence of DKD has remained relatively constant over the past three decades (despite progress in treating diabetic complications in general), and the chances of ending up with ESKD remains unacceptably high (2,3). Consequently, there has been much effort at identifying the underlying mechanisms that contribute to the progression of DKD, with the aim at developing novel therapeutic strategies. Such studies have led to the addition of new drugs, such as sodium-glucose cotransporter-2 inhibitors and selective nonsteroidal mineralocorticoid receptor antagonists to our therapeutic arsenal. Other agents (e.g., endothelin blockers, Nrf2 agonists, etc.) have also been investigated, but with varying degrees of success. It is clear, however, that our current therapeutic approaches are not universally or completely effective, nor devoid of adverse effects. Hence, the pursuit to uncover novel mechanisms and therapeutic targets continues. In this issue of Kidney360, Zheng et al. (4) examine whether endothelial specific molecule I (Esm-1), or Endocan, is one such potential target (Figure 1).Figure 1.: Proposed mechanism of podocyte protection by elevated endothelial specific molecule I (Esm-1). Increase Esm-1 in the glomerular microenvironment protects against podocytopathy by inhibiting macrophage-induced glomerular inflammation.Esm-1 is a 50 kD soluble proteoglycan secreted by vascular endothelial cells of several organs, and is present at low levels in the serum of healthy subjects. Its levels are higher in the kidney, predominantly in the glomeruli, raising the possibility that it may play a particularly important role in modulating glomerular, and consequently renal function and injury (5). Although Esm-1 is usually expressed at low levels under basal conditions, it is upregulated by numerous proinflammatory cytokines, including IL-1β and TNF-α, and in turn drives leukocyte extravasation through interactions with ICAM-1 and VCAM-1 (6). Hence, it is not surprising that its levels are elevated in conditions characterized by inflammation including renal and cardiovascular disorders such as hypertension, CKD, polycystic kidney disease, and kidney transplant rejection. In fact, Yilmaz et al. reported that higher levels of serum Esm-1 are found in advanced stages of CKD from all causes and are associated with an increased risk of cardiovascular death in patients with CKD. The concentrations of Esm-1 correlated positively with CKD stage and negatively with eGFR (7). This correlation has also been reported in recipients of kidney transplants with various degrees of renal graft failure (8). It must be noted, however, that although these studies suggest that ESM-1 may be a useful marker in CKD, they offer little insight into its contribution to the pathobiology of the disease process or the mechanisms by which it acts. Although the preponderance of studies suggests a role for Esm-1, at least as a biomarker of CKD, its role in DKD is much less clear. Esm-1 is increased in the plasma of patients with type 2 diabetes, particularly those with poorly controlled glycemia, is an independent risk factor for endothelial dysfunction, and has been reported to correlate with albuminuria (9,10). Moreover, adherence to American Diabetes Association guidelines reduced albuminuria and Esm-1 levels (10). However, unlike in other kidney and cardiovascular diseases, the associations between Esm-1 and DKD have been more contradictory (9,11), perhaps due to the multitude of inflammatory and other factors present in the diabetic milieu. This study by Zheng et al. advances our understanding of the role of Esm-1 in DKD; it provides strong evidence for its pathophysiologic role, introduced mechanistic insights into its actions, and furthers our understanding of its role as a biomarker in human DKD (4). The study is the logical extension of their previous one (5), where they found that induction of diabetes caused increases in glomerular ESM-1 (mRNA and protein). A key observation was that it increased less in DBA/2 mice, which are more susceptible to developing DKD, than in a strain of mice more resistant to DKD (C57BL/6 mice), thus raising the possibility that it was acting as a modulator, rather than just a marker of disease activity (i.e., an enhanced response in the DKD-susceptible animals would have been expected if it were merely a marker of disease activity). This potential for being a modulator was further supported by their studies in which they demonstrated that ESM-1 inhibited transmigration of leukocytes and increased leukocyte infiltration in DBA/2 mice as compared with DKD-resistant mice. These findings led the authors to hypothesize that Esm-1 is a modulator of renal injury in DKD, and that its relative deficiency in the DBA/2 mice contributed to their increased susceptibility to DKD. They tested this hypothesis by determining whether rescuing Esm-1 levels in DBA/2 diabetic mice (using overexpression strategies) ameliorated the development of renal injury. They then performed the reverse experiment in which they knocked out Esm-1 in DKD-resistant mice and to determine whether this would make them more susceptible to diabetic injury. The main findings of this study provide irrefutable evidence that Esm-1 can modulate renal injury in diabetic mice. Overexpressing it protected the DBA/2 mice against the development of albuminuria and podocyte foot process depletion, thus essentially changing their phenotype from a DKD-susceptible mouse strain to that of a DKD-resistant one. Whereas knocking out Esm-1 had the reverse effect; it increased the susceptibility of the C57BL/6 mice to DKD, basically transforming them into a DKD-susceptible strain. These changes were independent of any changes in glycemia or body weight, and thus appeared to be more directly linked to downstream mechanisms of renal injury. Because progressive diabetic nephropathy is associated with leukocyte accumulation in the glomeruli (12), and Esm-1 may attenuate leukocyte extravasation (13), the authors examined whether manipulating the expressing of ESM-1 altered glomerular leukocyte counts. The authors did find an inverse correlation between plasma Esm-1 levels and glomerular leukocyte infiltration. These findings are in agreement with a previous study showing that higher levels of Esm-1 correlated with decreased CD45+ glomerular leukocytes (13). However, overexpressing Esm-1 did not consistently decrease glomerular leukocytes, nor did glomerular leukocytes correlate with albuminuria in their model. Thus, the role of Esm-1 on leukocyte infiltration remains unclear. In contrast, despite the inconsistent effect on leukocytes, the transcriptomic studies suggest that Esm-1 is preventing diabetes-induced upregulation of several interferon-dependent pathways, thus suggesting that modulation of inflammatory pathways may still be implicated in the protective effect of Esm-1. In a final set of experiments, the authors attempt to extrapolate the rodent findings to humans. But their cross-sectional analysis failed to show a relationship between circulating Esm-1 levels and DKD. This appears to be in contrast with their rodent studies and previous human studies, which found that glomerular-enriched Esm-1 is relatively deficient in patients with DKD compared with healthy volunteers (5,14). This discrepancy may have been due to confounding factors, different contributions of Esm-1 generated by diverse organs to systemic ESM-1 levels, and the short follow-up duration. The inconsistency found in this and other studies raises the concern that simple measurement of systemic Esm-1 levels may not suffice to explain the localized effects of Esm-1 on the glomerular microenvironment, and would limit its usefulness as a simple biomarker. However, longitudinal changes in its expression in the plasma or urine may help assess risk of progression, or even serve as a marker of progression or responsiveness to therapy (as previously suggested) (10). Indeed, the authors provide preliminary evidence for this in their prospective cohort which was followed in a longitudinal manner. They found that lower levels of Esm-1 in patients with normo-albuminuria predicted progression to micro- or macroalbuminuria. These possibilities require further study. In conclusion, these studies suggest Esm-1 can be added to the list of adaptive mechanisms by which the kidney reacts in response to diverse injurious stimuli. It appears to act in a manner analogous to the heme oxygenase system, in which it is induced in response to cellular stress or injury, and then initiates signaling cascades that are protective in nature. Consequently, if its expression is enhanced, tissue injury is lessened, but if its expression is dampened, then tissue injury is exacerbated. Likewise, higher basal expression may confer extra resistance to the development of disease, whereas lower baseline expression may result in increased susceptibility to it. This study has elegantly demonstrated this effect and initiated an interrogation of the mechanisms involved. A full understanding of the patterns of expression, at both the local and systemic levels, and the mechanisms by which Esm-1 exerts its effects on the pathophysiology of the glomerular microenvironment during DKD is necessary for the development of potential therapeutic targets. This study is an important step in that direction. Disclosures L. Juncos reports having consultancy agreements with AstraZeneca, Fresenius/NxStage Critical Care, SeaStar Medical, and Vifor Pharmaceuticals; reports receiving honoraria from Fresenius Critical Care; and reports having an advisory or leadership role with the Editorial Boards of Frontiers in Pharmacology, JASN, and Kidney360. All remaining authors have nothing to disclose. Funding None.