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CD2-associated protein (CD2AP) expression in podocytes rescues lethality of CD2AP deficiency
James A Grunkemeyer1, Christopher Kwoh, Tobias B Huber
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Abstract:
Mice born without CD2-associated protein (CD2AP) develop renal failure and nephrotic syndrome about 4 weeks after birth and die around 6 weeks of age. Although CD2AP is widely expressed, the severity of the renal failure precludes a clear determination of the role of CD2AP in other tissues. Here we generated transgenic mice expressing CD2AP using a podocyte-specific promoter. Podocyte-specific expression of CD2AP prevented the development of proteinuria, demonstrating that the renal failure is solely due to loss of CD2AP in podocytes and not in other renal or in immune cells. CD2AP-deficient mice are long-lived and appear phenotypically normal. Histological analysis demonstrated testicular abnormalities that were age-related. CIN85, a paralog of CD2AP, is poorly expressed in both the podocyte and the basal seminiferous tubule, suggesting that the loss of CD2AP in specific tissues may be compensated for by CIN85.
Insights
Mice lacking CD2-associated protein (CD2AP) develop kidney failure. Podocyte-specific CD2AP expression prevents this, proving its critical role in kidney health.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- CD2-associated protein (CD2AP) is crucial for cellular functions.
- Mice lacking CD2AP experience severe renal failure and nephrotic syndrome early in life.
- The specific role of CD2AP in tissues beyond the kidney remains unclear due to early mortality.
Purpose of the Study:
- To determine if CD2AP's absence in podocytes alone causes renal failure.
- To investigate the function of CD2AP in other tissues.
- To explore the compensatory role of CIN85 in CD2AP-deficient tissues.
Main Methods:
- Generated transgenic mice with podocyte-specific CD2AP expression.
- Analyzed renal function, proteinuria, and survival rates.
- Performed histological analysis of kidneys and testes.
Main Results:
- Podocyte-specific CD2AP expression completely prevented proteinuria and renal failure.
- CD2AP-deficient mice that survived showed age-related testicular abnormalities.
- CIN85, a CD2AP paralog, showed low expression in podocytes and testes, suggesting limited compensation.
Conclusions:
- Renal failure in CD2AP-deficient mice is exclusively due to CD2AP loss in podocytes.
- CD2AP plays a vital, non-redundant role in podocyte function.
- CD2AP may have tissue-specific roles, with potential implications for testicular health.
