Piezo1 Mediates Vasodilation Induced by Acute Hyperglycemia in Mouse Renal Arteries and Microvessels

Abstract

Background: Acute hyperglycemia is a risk factor for developing acute kidney injury and poor renal outcome in critically ill patients, whereby the role of renal vasculature remains unclear. We hypothesize that hyperglycemia-associated hyperosmolarity facilitates vasodilation through Piezo1-mediated eNOS (endothelial NO synthase) activation. Methods: Vasoreactivity was analyzed using wire myography in isolated mouse mesenteric arteries and renal interlobar, and using microvascular perfusion in renal afferent arterioles and efferent arterioles, and vasa recta. Immunofluorescence and Western blot were used for molecular analyses of isolated mouse blood vessels and human umbilical vein endothelial cells. Results: Pretreatment with hyperglycemia (44 mmol/L glucose; 4 hours) increased acetylcholine-induced relaxation in interlobar arteries and mesenteric arteries, which was prevented by eNOS inhibition using Nω-nitro-L-arginine methylester hydrochloride. Hyperosmotic mannitol solution had a similar effect. Hyperglycemia induced an immediate, Nω-nitro-L-arginine methylester hydrochloride–inhibitable dilation in afferent arterioles, efferent arterioles, and vasa recta, whereby stronger dilation in afferent arterioles compared to efferent arterioles. Hyperglycemia also increased glomerular filtration rate in mice. In human umbilical vein endothelial cells, hyperglycemia, and the Piezo1 activator Yoda-1 increased levels of Piezo1 protein, p-CaMKII (phosphorylated Ca 2+ /Calmodulin-dependent protein kinase type II), Akt, and p-eNOS (phosphorylated eNOS). The hyperglycemia effect could be prevented by inhibiting Piezo1 using GsMTx4 ( Grammostola spatulata mechanotoxin 4) and CaMKII using KN93. Furthermore, in arteries and microvessels, inhibition of Piezo1 using GsMTx4 prevented the hyperglycemia –effect, while Yoda-1 caused relaxation and dilation, respectively. Conclusions: Results reveal that Piezo1 mediates renal vasodilation induced by hyperosmolarity in acute hyperglycemia. This mechanism may contribute to the pathogenesis of renal damage by acute hyperglycemia.

Mechanosensing by Piezo1 and its implications in the kidney

“…It has been found that in addition to podocytes, mesangial cells, and JG cells, capillary endothelial cells and parietal epithelial cells also express Piezo1 33,139 (Figure 2A and Table 3).…”

PIEZO Ion Channels in Cardiovascular Functions and Diseases

“…Its pivotal function as a hemodynamic force sensor not only confers endothelial PIEZO1 a critical role in maintaining physiological homeostasis under laminar flow but also in the development of vascular pathologies under high or turbulent flow (Figure 3B). It has been reported that PIEZO1 is upregulated in pulmonary arterial ECs during pulmonary hypertension, 76 and pharmacological manipulation of its activity has been reported to modulate vascular defects induced in models of vascular calcification, 77 hyperglycemia, 78 and pulmonary hypertension. 79 Moreover, PIEZO1 is directly involved in atherosclerosis, 54 a common condition corresponding to a slowly worsening chronic inflammatory disease (Figure 3B).…”

Paradigm Shift in Hyperglycemic Glomerular Hyperfiltration: Blunted Tubuloglomerular Feedback or Preglomerular Vasodilation?

“…5 However, is impaired autoregulation in hyperglycemia solely caused by a blunted tubuloglomerular feedback response? This traditional concept is challenged by paradigm-shifting findings by Fei et al 4 Using stateof-the-art microvascular perfusion and myography, the authors discovered that acute hyperglycemia induced profound afferent arteriolar vasodilation and glomerular hyperfiltration, as evidenced by markedly enhanced glomerular filtration rate, through a novel pathway involving Piezo1, CaMKII (Ca2 + /calmodulin-dependent protein kinase type II), and eNOS (endothelial NO synthase; Figure ).…”

“…Blunted tubuloglomerular feedback was considered the chief cause of hyperglycemic glomerular hyperfiltration, but this paradigm may need to change. In this issue of Hypertension, Fei et al 4 made an intriguing discovery that high glucose can increase glomerular filtration rate through direct vasodilatory effects in renal resistance vessels.…”