Biology subjects

Marciszyn, A. L.

Publications and source records attributed to Marciszyn, A. L..

3 recordsLinked to original sources

bioRxiv2021

Kidney-Specific WNK1 Amplifies NCC Responsiveness to Potassium Imbalance

To maintain potassium homeostasis, the kidneys distal convoluted tubule (DCT) converts small changes in blood [K+] into robust effects on salt reabsorption. This process requires NaCl cotransporter (NCC) activation by WNK kinases. During hypokalemia, the Kidney-Specific WNK1 isoform (KS-WNK1) scaffolds the DCT-expressed WNK signaling pathway within biomolecular condensates of unknown function termed WNK bodies. Here, we show that KS-WNK1 amplifies the dynamic range of NCC activity in response to potassium imbalance, in part via WNK bodies. Targeted condensate disruption traps the WNK pathway, causing renal salt-wasting that is more pronounced in females. In humans, WNK bodies accumulate as plasma potassium falls below 4.0mmol/L, suggesting avid condensate-mediated salt reabsorption even when [K+] is low-normal. These data identify WNK bodies as signal amplifiers that mediate tubular potassium responsiveness, nephron sexual dimorphism, and blood pressure salt-sensitivity. Our results illustrate how condensate specialization can optimize a mammalian physiologic stress response that impacts human health.

physiology↗

bioRxiv2021

L-WNK1 is required for BK channel activation in intercalated cells

BK channels expressed in intercalated cells (ICs) in the aldosterone-sensitive distal nephron (ASDN) mediate flow-induced K+ secretion. In the ASDN of mice and rabbits, IC BK channel expression and activity increase with a high K+ diet. In cell culture, the long isoform of the kinase WNK1 (L-WNK1) increases BK channel expression and activity. Apical L-WNK1 expression is selectively enhanced in ICs in the ASDN of rabbits on a high K+ diet, suggesting that L-WNK1 contributes to BK channel regulation by dietary K+. We examined the role of IC L-WNK1 expression in enhancing BK channel activity in response to a high K+ diet. Mice with an IC-selective deletion of L-WNK1 (IC-L-WNK1-KO) and littermate control mice were placed on a high K+ (5% K+ as KCl) diet for at least 10 days. IC-L-WNK1-KO mice exhibited higher blood K+ concentrations ([K+]) than controls. BK channel-dependent whole-cell currents in ICs from cortical collecting ducts of high K+ fed IC-L-WNK1-KO mice were reduced compared to controls. Six-hour urinary K+ excretion in response a saline load was similar in IC-L-WNK1-KO mice and controls. The observations that IC-L-WNK1-KO mice have higher blood [K+] and reduced IC BK channel currents are consistent with impaired urinary K+ secretion, and suggest that IC L-WNK1 has a role in the renal adaptation to a high K+ diet.

physiology↗

bioRxiv2021

Water and Electrolyte Homeostasis in a Mouse Model with Reduced ENaC Gamma Subunit Expression

The epithelial Na+ channel (ENaC) promotes the absorption of Na+ in the aldosterone-sensitive distal nephron, colon, and respiratory epithelia. Deletion of genes encoding ENaCs subunits results in early post-natal mortality. We present initial characterization of a mouse with dramatically suppressed expression of the {gamma} subunit. We use this hypomorphic ({gamma}mt) allele to explore the importance of ENaCs {gamma} subunit in homeostasis of electrolytes and body fluid volume. At baseline, {gamma} subunit expression in {gamma}mt/mt mice is markedly suppressed in kidney and lung, while electrolytes resemble those of littermate controls. Challenge with a high K+ diet does not cause significant differences in blood K+, but provokes higher aldosterone in {gamma}mt/mt mice than controls. Quantitative magnetic resonance (QMR) measurement of body composition reveals similar baseline body water, lean tissue mass, and fat tissue mass in {gamma}mt/mt mice and controls. Surprisingly, euvolemia is sustained without significant changes in aldosterone or atrial natriuretic peptide. {gamma}mt/mt mice exhibit a more rapid decline in body water and lean tissue mass in response to a low Na+ diet than controls. Replacement of drinking water with 2% saline induces dramatic increases in body fat in both genotypes, and a selective transient increase in body water and lean tissue mass in {gamma}mt/mt mice. While ENaC in renal tubules and colon work to prevent extracellular fluid volume depletion, our observations suggest that ENaC in non-epithelial tissues may have a role in preventing extracellular fluid volume overload.

physiology↗