Bradykinin Stimulates Renal Na ⁺ and K ⁺ Excretion by Inhibiting the K ⁺ Channel (Kir4.1) in the Distal Convoluted Tubule

Abstract

Stimulation of BK2R (bradykinin [BK] B2 receptor) has been shown to increase renal Na excretion. The aim of the present study is to explore the role of BK2R in regulating Kir4.1 and NCC (NaCl cotransporter) in the distal convoluted tubule (DCT). Immunohistochemical studies demonstrated that BK2R was highly expressed in both apical and lateral membrane of Kir4.1-positive tubules, such as DCT. Patch-clamp experiments demonstrated that BK inhibited the basolateral 40-pS K channel (a Kir4.1/5.1 heterotetramer) in the DCT, and this effect was blocked by BK2R antagonist but not by BK1R (BK B1 receptor) antagonist. Whole-cell recordings also demonstrated that BK decreased the basolateral K conductance of the DCT and depolarized the membrane. Renal clearance experiments showed that BK increased urinary Na and K excretion. However, the BK-induced natriuretic effect was completely abolished in KS-Kir4.1 KO (kidney-specific conditional Kir4.1 knockout) mice, suggesting that Kir4.1 activity is required for BK-induced natriuresis. The continuous infusion of BK with osmotic pump for 3 days decreased the basolateral K conductance and the negativity of the DCT membrane. Western blot showed that infusion of BK decreased the expression of total NCC and phosphorylated NCC. Renal clearance experiments demonstrated that thiazide-induced natriuresis was blunted in the mice receiving BK infusion, suggesting that BK inhibited NCC function. Consequently, mice receiving BK infusion for 3 days were hypokalemic. We conclude that stimulation of BK2R inhibits NCC activity, increases urinary K excretion, and causes mice hypokalemia and that Kir4.1 is required for BK2R-mediated stimulation of urinary Na and K excretion.

A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm

“…Furthermore, excess BK can lead to hypokalemia ( Zhang et al, 2018 ), which is associated with arrhythmia and sudden cardiac death ( Kjeldsen, 2010 ), ( Bielecka-Dabrowa et al, 2012 ; Skogestad and Aronsen, 2018 ) , both of which have been reported in COVID-19 patients ( Huang et al, 2020 ; Guo et al, 2020 ), ( Wang et al, 2020 ) ; a recent report confirms that hypokalemia is occurring in severe cases of COVID-19 ( Lippi et al, 2020 ). It is also notable that many of the other symptoms being reported for COVID-19 (myalgia, fatigue, nausea, vomiting, diarrhea, anorexia, headaches, decreased cognitive function) are remarkably similar to other hyper-BK-conditions that lead to vascular hyper-permeabilization such as angioedema as was recently noted ( van de Veerdonk et al, 2020 ).…”

Repurposed Drugs, Molecular Vaccines, Immune‐Modulators, and Nanotherapeutics to Treat and Prevent COVID‐19 Associated with SARS‐CoV‐2, a Deadly Nanovector

“…The bradykinin storm induced leakage of fluid and hyaluronic acid induced formation of hydrogel into the lungs may be the reason behind low oxygen uptake in severe COVID-19 patients and generation of severe symptoms like hypokalemia associated with arrhythmia and sudden cardiac death. [42][43][44][45] Hence, the drugs which can take care of the bradykinin storm can also be considered as potential therapeutics for COVID-19. SARS-CoV-2 phylogenetic analysis showed that it is meticulously related to two bat-derived SARS-like CoVs (bat-SL-CoVZC45 and bat-SL-CoVZXC21) found in horseshoe bats (Rhinolophus) with ≈89% nucleotide sequence resemblance with bat-SL-CoVZC45.…”

Intracellular chloride

“…Interestingly, while Kir4.1/5.1 is the sole potassium conductance on the basolateral membrane of the DCT, it coexists with other potassium channels on the basolateral thick ascending limb [113]. This may make the DCT more sensitive to hormonal regulators of Kir4.1/5.1, such as bradykinin or angiotensin II [114,115].…”