Two independent modes of kidney stone suppression achieved by AIM/CD5L and KIM-1
Kyohei Matsuura1, Natsumi Maehara1,2, Aika Hirota1,2
1Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
Abstract:
The prevalence of kidney stones is increasing and its recurrence rate within the first 5 years is over 50%. No treatments that prevent the occurrence/recurrence of stones have reached the clinic. Here, we show that AIM (also called CD5L) suppresses stone development and improves stone-associated physical damages. The N-terminal domain of AIM associates with calcium oxalate crystals via charge-based interaction to impede the development of stones, whereas the 2nd and C-terminal domains capture the inflammatory DAMPs to promote their phagocytic removal. Accordingly, when stones were induced by glyoxylate in mice, recombinant AIM (rAIM) injection dramatically reduced stone development. Expression of injury molecules and inflammatory cytokines in the kidney and overall renal dysfunction were abrogated by rAIM. Among various negatively charged substances, rAIM was most effective in stone prevention due to its high binding affinity to crystals. Furthermore, only AIM was effective in improving the physical complaints including bodyweight-loss through its DAMPs removal effect. We also found that tubular KIM-1 may remove developed stones. Our results could be the basis for the development of a comprehensive therapy against kidney stone disease.
Insights
AIM protein (also known as CD5L) suppresses kidney stone development and reduces associated physical damage. This discovery offers a new therapeutic avenue for preventing kidney stone recurrence.
Area of Science:
- Nephrology
- Immunology
- Biochemistry
Background:
- Kidney stone prevalence is rising, with over 50% recurrence within 5 years.
- Current treatments lack efficacy in preventing stone occurrence or recurrence.
- AIM (CD5L) is investigated for its potential role in kidney stone management.
Purpose of the Study:
- To investigate the stone-suppressing and damage-repairing capabilities of AIM.
- To elucidate the molecular mechanisms by which AIM interacts with calcium oxalate crystals and inflammatory molecules.
- To evaluate the therapeutic potential of recombinant AIM (rAIM) in a mouse model of kidney stones.
Main Methods:
- Induction of kidney stones in mice using glyoxylate.
- Administration of recombinant AIM (rAIM) to assess its effects on stone development.
- Analysis of kidney injury markers, inflammatory cytokines, and renal function.
- In vitro assessment of AIM's binding affinity to calcium oxalate crystals and other negatively charged substances.
- Evaluation of AIM's effect on physical complaints, including body weight loss.
Main Results:
- rAIM injection significantly reduced kidney stone development in mice.
- rAIM administration abrogated the expression of kidney injury molecules and inflammatory cytokines, improving renal function.
- AIM demonstrated high binding affinity to calcium oxalate crystals, outperforming other negatively charged substances in stone prevention.
- AIM effectively alleviated physical symptoms like body weight loss through the removal of damage-associated molecular patterns (DAMPs).
- Tubular KIM-1 was identified as a potential factor in removing developed stones.
Conclusions:
- AIM effectively suppresses kidney stone formation and mitigates associated renal damage and dysfunction.
- AIM's dual mechanism involving crystal binding and DAMPs removal offers a novel therapeutic strategy.
- These findings provide a foundation for developing comprehensive therapies for kidney stone disease.
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