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Klotho Protects Against Indoxyl Sulphate-Induced Myocardial Hypertrophy
Ke Yang1, Cheng Wang2, Ling Nie1
1Department of Nephrology, Institute of Nephrology of Chongqing and Kidney Center of People's Liberation Army, Xinqiao Hospital.
Insights
Klotho protein protects against left ventricular hypertrophy (LVH) in chronic kidney disease (CKD) by counteracting the harmful effects of indoxyl sulfate (IS). Imbalances between Klotho and IS contribute to LVH development in CKD patients.
Area of Science:
- Nephrology
- Cardiology
- Molecular Biology
Background:
- Left ventricular hypertrophy (LVH) is a significant complication and mortality risk factor in chronic kidney disease (CKD).
- The roles of uremic solutes like indoxyl sulfate (IS) and Klotho in CKD-associated LVH are not fully understood.
- Investigating the interplay between IS and Klotho is crucial for understanding LVH pathogenesis in CKD.
Purpose of the Study:
- To investigate the interaction between Klotho and indoxyl sulfate (IS) in the context of CKD-associated LVH.
- To determine the protective role of Klotho against IS-induced LVH.
- To explore the potential therapeutic implications of targeting the Klotho-IS axis in CKD.
Main Methods:
- Clinical study of 86 CKD patients to assess serum levels of IS, Klotho, and LVH.
- In vivo experiments using normal and Klotho-deficient mice treated with IS to induce and evaluate LVH.
- In vitro studies using cell cultures to examine the effects of Klotho on IS-induced cardiomyocyte hypertrophy.
- Therapeutic intervention in a CKD mouse model using Klotho protein administration.
Main Results:
- A negative correlation was observed between serum IS and Klotho levels in CKD patients.
- Both elevated IS and reduced Klotho were independently associated with LVH in CKD.
- IS administration induced LVH and downregulated renal Klotho in mice, with exacerbated LVH in Klotho-deficient mice.
- Klotho inhibited IS-induced cardiomyocyte hypertrophy in vitro by blocking oxidative stress and specific signaling pathways.
- Klotho protein treatment significantly attenuated LVH in a CKD mouse model.
Conclusions:
- Klotho acts as an endogenous protector against indoxyl sulfate-induced left ventricular hypertrophy.
- The imbalance between Klotho and IS plays a critical role in the development of LVH in chronic kidney disease.
- Restoring Klotho levels or function may represent a therapeutic strategy for managing LVH in CKD patients.
Abstract:
Left ventricular hypertrophy (LVH) is a common complication in patients with CKD and an independent risk factor for death. Changes in the levels of uremic solutes or Klotho have been reported to be related to CKD, whereas the relationships between these factors and CKD-associated LVH remain unclear. Here, we investigated the interaction between Klotho and indoxyl sulfate (IS), a typical uremic solute, in CKD-associated LVH. In a survey of 86 patients with CKD, a negative relationship was found between serum levels of IS and Klotho (r=-0.59, P<0.001). Furthermore, serum levels of IS and Klotho were independently associated with LVH (for IS: r=0.69, P<0.001; for Klotho: r=-0.49, P<0.001). In normal mice, intraperitoneal injection of IS for 8 weeks induced LVH accompanied by substantial downregulation of renal Klotho. Notably, IS-induced LVH was more severe in heterozygous Klotho-deficient (kl/+) mice. In vitro, treatment with Klotho strongly inhibited IS-induced cardiomyocyte hypertrophy by blocking oxidative stress and inhibiting p38 and extracellular signal-regulated protein kinase 1/2 signaling pathways. In a mouse model of CKD-associated LVH, the renal expression of Klotho was lower and the level of serum IS was higher than in healthy controls. Moreover, treatment of CKD mice with Klotho protein significantly restrained the development of LVH. Taken together, these results suggest that Klotho is an endogenous protector against IS-induced LVH, and the imbalance between Klotho and IS may contribute to the development of LVH in CKD.
