Roles of Klotho and Endothelin-1 in pseudoexfoliation

Serum and aqueous levels of Klotho levels are reduced in pseudoexfoliation syndrome (PXF) and pseudoexfoliative glaucoma (PEG) while Endothelin-1 (ET-1) is increased, researchers say.

“These findings support the hypothesis that Klotho deficiency may play an important role in the occurrence and severity of [PXF] and even its progression to PEG, caused, at least in part by the accelerating aging process,” Mohammad H. Ahoor and colleagues from Tabriz University of Medical Science in Tabriz, Iran report in the Journal of Glaucoma.

Discovered in 1997, Klotho plays an important role in the health of endothelial cells. Levels of Klotho correlate with age, and PXF and PEG are both age-related diseases. Klotho has been associated with age-related kidney damage and, in animal models, with diabetes and hypertension.

Meanwhile, ET-1 acts as a vasoconstrictor in the regulation of ocular blood flow and the trabecular network contraction to control IOP, as well as contracting the ciliary muscle.

Given the role of impaired endothelial cell function and oxidative stress in the pathogenesis of PXF, Ahoor and colleagues hypothesized that low serum and aqueous humor Klotho and high serum and aqueous humor ET-1 levels might be found in PXF or PEG.

A common age-related fibrillopathy, PXF is the most common clinical precursor of open-angle glaucoma. Recent research has implicated impaired function of endothelial cells and oxidative stress in its pathogenesis.

To investigate, the researchers recruited 45 patients with senile cataract, of whom 15 had PXF, 15 had PEG, and 15 served as controls. The patients ranged from 40 to 70 years of age.

Patients were excluded if they had a best-corrected visual acuity of less than 20/80, an IOP greater than 21 mm Hg with or without drug treatment, a history of ocular surgery, or several other categories of eye disease and systemic illness.

Serum, aqueous levels

The researchers found that the mean serum level of Klotho was 50.49 ng/mL in the PEG group, 56.32 ng/mL in the PXF group, and 65.06 ng/mL in the control group. The mean aqueous level of Klotho was 34.53 ng/mL in the PEG group, 49.02 ng/mL in the PXF group, and 56.31 ng/mL in the control group.

These differences between PEG on one hand and PXF and control for both serum and aqueous levels were statistically significant (P = 0.001-0.003). Likewise, the comparisons between PXF and control was significant (P = 0.006 for aqueous and 0.004 for serum).

The mean serum level of ET-1 was 1.66 pg/mL in the PXF patients, 1.58 in the PEG patients and 1.16 pg/mL in the control patients. The mean aqueous level of ET-1 was 1.45 in the PEG patients, 1.28 pg/mL in the PXF patients, and 1.17 pg/mL in the control group.

The serum and aqueous ET-1 difference between the PXF group and the control group, and between the PEG group and the control group were both statistically significant (P = 0.01). The difference in serum ET-1 levels was not significant between the PEG and PXF groups. However, the difference in aqueous ET-1 levels was significant between the PEG and PXF groups (P = 0.04).

The researchers also found a negative correlation between the aqueous levels of Klotho and the severity of PXF (correlation coefficient [CC] = -0.68, P = 0.01). They did not find any correlation between the severity of PXF and ET-1 aqueous levels (CC = 0.05, P = 0.86).

Using cup-to-disc ratio, they found a negative correlation between the severity of glaucoma and aqueous Klotho levels (CC = -0.57, P = 0.01) and a positive correlation between aqueous ET-1 and the severity of glaucoma (CC = 0.55, P = 0.01).

The finding fits well into the pattern of previous research. Studies have found that Klotho protects against cardiovascular and renal disease, perhaps due to its antioxidant effect. It appears to play a role in preventing age-related macular degeneration, and to protect retinal pigmented epithelium cells.

Other researchers have reported that levels of ET-1, and the numbers of endothelin A and endothelin B receptors increased dramatically in patients with normal tension glaucoma. They have found that plasma levels of ET-1 significantly increase in patients with progressive open-angle glaucoma.

Ahoor and colleagues acknowledged some limitations of their study. First, all the patients had senile cataract, which might affect Klotho levels. They tried to minimize this potentially confounding factor by selecting patients with the same grade of cataract for all groups. Still, total Klotho levels might be underestimated in all these groups, they pointed out.

Second, the study had small sample sizes and its cross-sectional design prevented it from showing whether serum and aqueous Klotho and ET-1 concentrations were predictive for the progression of PXF and PEG.

They called for further research aimed at determining the potential of Klotho to protect against PXF and PEG.