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Decreased KLHL3 expression is involved in the activation of WNK-OSR1/SPAK-NCC cascade in type 1 diabetic mice

  • Ion channels, receptors and transporters
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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.

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Abbreviations

FHHt:

Familial hyperkalemic hypertension

KLHL3:

Kelch-like3

CUL3:

Cullin3

GLUT:

glucose transporter

NCC:

Na-Cl cotransporter

PKC:

Protein kinase C

PKA:

Protein kinase A

NKCC:

Na–K–Cl cotransporter

T2DM:

type 2 diabetes mellitus

PM:

Plasma membrane

OSR1:

Oxidative stress response kinase-1

SPAK:

STE20/SPS1-related proline alanine–rich kinase

TBC1D:

Tre-2-BUB2-CDC16 domain family member

WNK kinase:

With-no-lysine protein kinase

T1DM:

Type 1 diabetes mellitus

HCTZ:

Hydrochlorothiazide

HG:

High glucose

LG:

Low glucose

LM:

Low mannitol

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Acknowledgments

We thank Chao-Ling Yang and David H. Ellison from Oregon Health and Science University for providing antibodies used in this study.

Funding

This work was supported by a grant from the National Natural Science Foundation of China (No 81770706 and 81570634).

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  1. Department of Nephrology, Shanghai Xinhua Hospital, Jiao Tong University School of Medicine, Shanghai, 200092, China

    Qin Guo, Ya Zhang, Geng-Ru Jiang & Chong Zhang

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Guo, Q., Zhang, Y., Jiang, GR. et al. Decreased KLHL3 expression is involved in the activation of WNK-OSR1/SPAK-NCC cascade in type 1 diabetic mice. Pflugers Arch - Eur J Physiol 473, 185–196 (2021). https://doi.org/10.1007/s00424-020-02509-8

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