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Published on: January 4, 2018
Decreased KLHL3 expression is involved in the activation of WNK-OSR1/SPAK-NCC cascade in type 1 diabetic mice
Qin Guo1, Ya Zhang1, Geng-Ru Jiang2
1Department of Nephrology, Shanghai Xinhua Hospital, Jiao Tong University School of Medicine, Shanghai, 200092, China.
Abstract:
Familial hyperkalemic hypertension (FHHt; also called pseudohypoaldosteronism type II) is a hereditary hypertensive disease which can be caused by mutations in four genes: WNK1 [with no lysine (K) 1], WNK4, Kelch-like3 (KLHL3), and cullin3 (CUL3). Decreased KLHL3 expression was identified as being involved in the pathogenesis of FHHt caused by cullin 3 disease mutations. Recent studies have revealed an increased WNK4 and hence Na-Cl cotransporter (NCC) activity in the db/db mice, resulting from PKC-mediated KLHL3 phosphorylation, which impairs the degradation of its substrate, WNK4. However, whether WNK4 and NCC were activated in type 1 diabetes still remains unclear. We created streptozotocin-induced type 1 diabetic mice and revealed that renal WNK-oxidative stress response kinase-1/STE20/SPS1-related proline alanine-rich kinase (OSR1/SPAK)-NCC cascade was activated, whereas KLHL3 expression was markedly decreased and CUL3 was heavily neddylated. Moreover, decreased KLHL3 was reversed and WNK1 and WNK4 abundance increased by MLN4924, a neddylation inhibitor. In vitro, our study also showed decreased KLHL3 abundance without any significant change in phosphorylated KLHL3 under high glucose exposure. These results indicate that decreased KLHL3 likely plays a role in the pathogenesis of renal sodium reabsorption in hyperglycemic conditions.
Insights
Familial hyperkalemic hypertension involves WNK1, WNK4, KLHL3, and CUL3 genes. In type 1 diabetes, decreased KLHL3 and activated WNK-NCC cascade contribute to renal sodium reabsorption issues.
Area of Science:
- Nephrology
- Endocrinology
- Genetics
Background:
- Familial hyperkalemic hypertension (FHHt) is a genetic disorder linked to WNK1, WNK4, KLHL3, and CUL3 mutations.
- KLHL3 dysfunction impairs WNK4 degradation, increasing WNK4 and NCC activity, a mechanism observed in obesity models.
- The role of WNK4 and NCC activation in type 1 diabetes remains largely unexplored.
Purpose of the Study:
- To investigate the activation of the WNK-OSR1/SPAK-NCC cascade in type 1 diabetes.
- To examine the expression of KLHL3 and CUL3 neddylation in a type 1 diabetes mouse model.
- To explore the potential therapeutic effects of neddylation inhibition on WNK pathway components.
Main Methods:
- Induction of type 1 diabetes in mice using streptozotocin.
- Assessment of renal WNK-OSR1/SPAK-NCC cascade activation.
- Analysis of KLHL3 expression and CUL3 neddylation.
- In vitro studies on KLHL3 expression under high glucose conditions.
- Treatment with MLN4924, a neddylation inhibitor.
Main Results:
- Type 1 diabetes mice exhibited activation of the renal WNK-OSR1/SPAK-NCC cascade.
- Markedly decreased KLHL3 expression and increased CUL3 neddylation were observed in diabetic kidneys.
- MLN4924 treatment reversed decreased KLHL3 and increased WNK1 and WNK4 abundance.
- In vitro, high glucose reduced KLHL3 abundance without affecting its phosphorylation.
Conclusions:
- Decreased KLHL3 expression is implicated in the pathogenesis of renal sodium reabsorption in hyperglycemic conditions.
- The WNK-OSR1/SPAK-NCC pathway is activated in type 1 diabetes, potentially contributing to hypertension.
- Targeting neddylation may offer a therapeutic strategy for managing renal sodium handling abnormalities in diabetes.
