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Updated: Aug 24, 2026
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Differential expression of calcineurin A isoforms in the diabetic kidney
Jennifer L Gooch1, Pablo E Pèrgola, Rebecca L Guler
1Department of Medicine, Division of Nephrology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. Gooch@uthscsa.edu
Abstract:
Calcineurin is an important signaling molecule in mesangial cells in vitro and is involved in some manifestations of diabetic nephropathy in vivo. However, calcineurin acts in a cell-specific and tissue-specific manner in the kidney, and mechanisms of specificity are unknown. Three closely related isoforms of the calcineurin A (CnA) subunit are expressed in a tissue-specific manner. This study was undertaken to determine if specificity of calcineurin action is linked to regulation of CnA isoforms in the diabetic kidney. After induction of diabetes with streptozotocin, expression of all three CnA isoforms rapidly increased, primarily in the thick ascending limb of Henle (TAL). After prolonged diabetes, increase specifically of the alpha isoform was observed in collecting ducts (CD) and in endothelial cells of glomeruli. Aquaporin 2 (AQP2), a putative substrate of calcineurin phosphatase in the kidney, is also involved in diabetic nephropathy. Co-localization of CnA isoforms with AQP2 revealed that CnA-alpha is the predominant isoform that associates with AQP2 in the diabetic kidney. Furthermore, inhibition of calcineurin with cyclosporin A (CsA) alters AQP2 localization and phosphorylation in principal cells of CD. Alterations in subcellular localization of AQP2 were parallel with CnA-alpha. Similarly, CsA treatment results in a further increase in urine output compared with diabetes alone, suggesting a functional consequence of inhibiting calcineurin-mediated regulation of AQP2. In conclusion, all three isoforms of CnA are upregulated in the diabetic kidney. Increased expression of CnA-alpha, in particular, is observed in glomeruli and CD and participates in regulation of AQP2 expression, phosphorylation, and function.
Insights
Calcineurin (CnA) isoforms are upregulated in diabetic kidneys, with CnA-alpha specifically regulating aquaporin 2 (AQP2) in glomeruli and collecting ducts, impacting kidney function in diabetic nephropathy.
Area of Science:
- Nephrology
- Molecular Biology
- Endocrinology
Background:
- Calcineurin is a key signaling molecule implicated in diabetic nephropathy.
- The cell-specific and tissue-specific actions of calcineurin in the kidney remain poorly understood.
- Three distinct calcineurin A (CnA) subunit isoforms exhibit tissue-specific expression patterns.
Purpose of the Study:
- To investigate if calcineurin specificity in the diabetic kidney is linked to the regulation of its CnA isoforms.
- To determine the role of specific CnA isoforms in the context of diabetic nephropathy and aquaporin 2 (AQP2) regulation.
Main Methods:
- Induction of diabetes using streptozotocin in a rodent model.
- Analysis of CnA isoform expression in kidney tissues at different stages of diabetes.
- Co-localization studies of CnA isoforms with AQP2.
- Pharmacological inhibition of calcineurin using cyclosporin A (CsA) and assessment of its effects on AQP2 and urine output.
Main Results:
- All three CnA isoforms were rapidly upregulated in the diabetic kidney, particularly in the thick ascending limb of Henle (TAL).
- Prolonged diabetes led to a specific increase in CnA-alpha expression in collecting ducts (CD) and glomerular endothelial cells.
- CnA-alpha was found to be the predominant isoform associated with AQP2 in the diabetic kidney.
- CsA treatment altered AQP2 localization and phosphorylation in CD principal cells, mirroring CnA-alpha's subcellular changes.
- CsA treatment exacerbated the increase in urine output in diabetic animals compared to diabetes alone.
Conclusions:
- All three CnA isoforms are upregulated in the diabetic kidney.
- CnA-alpha expression is particularly elevated in glomeruli and CD in diabetic conditions.
- CnA-alpha plays a significant role in regulating AQP2 expression, phosphorylation, and function, contributing to diabetic nephropathy.
