Rapid development of vasopressin resistance in dietary K⁺ deficiency

Abstract

The association between diabetes insipidus (DI) and chronic dietary potassium deprivation is well known but it remains uncertain how the disorder develops and whether it is influenced by the sexual dimorphism in potassium handling. Here, we determine the plasma potassium (PK) threshold for DI in male and female mice and ascertain if the DI is initiated by polydipsia, or a central or nephrogenic defect. C57BL6J mice were randomized to a control diet or to graded reductions in dietary K+ for 8 days, and kidney function and transporters involved in water balance were characterized. We found male and female mice develop polyuria and secondary polydipsia. Altered water balance coincides with a decrease in AQP2 phosphorylation and apical localization despite increased levels of the vasopressin surrogate marker, copeptin. No change in the protein abundance of the urea transporter, UT-A1, was observed. NKCC2 decreased only in males. DDAVP treatment failed to reverse water diuresis in K+-restricted mice. These findings indicate that even small fall in PK is associated with nephrogenic DI (NDI), coincident with the development of altered AQP2 regulation, implicating low PK as a causal trigger of NDI. We found PK decreased more in females, and consequently females were more prone to develop NDI. Together these data indicate that AQP2 regulation is disrupted by a small decrease in PK and the response is influenced by sexual dimorphism in potassium handling. These findings provide new insights into the mechanisms linking water and potassium balances, and support defining the disorder as "Potassium-Dependent NDI."

HDAC3 inhibition improves urinary‐concentrating defect in hypokalaemia by promoting AQP2 transcription

“…32 Hypokalaemia is associated with impaired vasopressin regulation, and the inhibition of HDACs in vivo might affect the vasopressin signalling pathway. 12 However, RGFP966 treatment showed no effect on cAMP excretion in HK rats; the increased AQP2 protein level associated with RGFP966 treatment is thus likely attributable to mechanisms other than vasopression-cAMP signalling pathway activation. The interstitial osmolality in the inner medullae is another factor associated with AQP2 protein expression.…”

“…Interestingly, increased urinary cAMP excretion was also seen in lithium‐induced NDI 32 . Hypokalaemia is associated with impaired vasopressin regulation, and the inhibition of HDACs in vivo might affect the vasopressin signalling pathway 12 . However, RGFP966 treatment showed no effect on cAMP excretion in HK rats; the increased AQP2 protein level associated with RGFP966 treatment is thus likely attributable to mechanisms other than vasopression‐cAMP signalling pathway activation.…”

“…Vasopressin resistance has been known in hypokalaemia 12 ; therefore, we next measured the urinary cAMP levels in HK rats treated with or without RGFP966 to identify whether HDAC3 inhibition affects the vasopressin signalling pathway. The HK rats showed increased urinary cAMP excretion rate compared with controls, RGFP966 treatment reduced urinary cAMP excretion but did not reach statistical significance (Figure 8F), indicating that the impaired vasopressin-cAMP pathway was unlikely rescued by HDAC3 inhibition.…”

KCC3a, a Strong Candidate Pathway for K+ Loss in Alkalemia

“…Similarly, long-term K + depletion is known to result in nephrogenic diabetes insipidus and the production of a large amount of urine ( Marples et al, 1996 ; Oksche and Rosenthal, 1998 ; Boyd-Shiwarski et al, 2020 ). In mice, a long-term K + -free diet also causes an increase in water excretion ( Boyd-Shiwarski et al, 2020 ; Al-Qusairi et al, 2021 #4628). Plasma osmolarity, plasma Na + , and electrolyte-free water clearance are higher on K + -free diet than on a control K + diet.…”

Low Salt Delivery Triggers Autocrine Release of Prostaglandin E2 From the Aldosterone-Sensitive Distal Nephron in Familial Hyperkalemic Hypertension Mice

“…Tissue dissection, storage and preparation for western blots (WBs) were performed as previously described ( Al-Qusairi et al, 2021 ). Briefly, cortex and medulla tissues were snap frozen in liquid nitrogen and then stored at −80°C until use.…”