Nitric Oxide Signalling in Descending Vasa Recta after Hypoxia/Re-Oxygenation

Abstract

Reduced renal medullary oxygen supply is a key factor in the pathogenesis of acute kidney injury (AKI). As the medulla exclusively receives blood through descending vasa recta (DVR), dilating these microvessels after AKI may help in renoprotection by restoring renal medullary blood flow. We stimulated the NO-sGC-cGMP signalling pathway in DVR at three different levels before and after hypoxia/re-oxygenation (H/R). Rat DVR were isolated and perfused under isobaric conditions. The phosphodiesterase 5 (PDE5) inhibitor sildenafil (10−6 mol/L) impaired cGMP degradation and dilated DVR pre-constricted with angiotensin II (Ang II, 10−6 mol/L). Dilations by the soluble guanylyl cyclase (sGC) activator BAY 60-2770 as well as the nitric oxide donor sodium nitroprusside (SNP, 10−3 mol/L) were equally effective. Hypoxia (0.1% O2) augmented DVR constriction by Ang II, thus potentially aggravating tissue hypoxia. H/R left DVR unresponsive to sildenafil, yet sGC activation by BAY 60-2770 effectively dilated DVR. Dilation to SNP under H/R is delayed. In conclusion, H/R renders PDE5 inhibition ineffective in dilating the crucial vessels supplying the area at risk for hypoxic damage. Stimulating sGC appears to be the most effective in restoring renal medullary blood flow after H/R and may prove to be the best target for maintaining oxygenation to this vulnerable area of the kidney.

Understanding human aging and the fundamental cell signaling link in age-related diseases: the middle-aging hypovascularity hypoxia hypothesis

“…Hypoxia in chronic kidney disease ( Faivre et al, 2021 ; Wang B. et al, 2022 ) has been well studied and is used here to highlight the middle-aged (>50 years) ( Ryu et al, 2019 ) hypovascularity ( Fine and Norman, 2008 ; Evans et al, 2020 ; Querfeld et al, 2020 ) hypoxia ( Faivre et al, 2021 ; Wang L. et al, 2022 ) pathological trajectories in linking the endocrine system ( Zhao and Schooling, 2020 ; Li L. et al, 2022 ; Romejko et al, 2022 ), nitric oxide signaling, and oxygen homeostasis pathophysiology ( Burmakin et al, 2021 ; Carlström, 2021 ; Xu M. et al, 2022 ; Edwards and Kurtcuoglu, 2022 ). Oxidative stress–inflammation pathophysiology ( Ebert et al, 2021 ), amyloidosis ( Ryu et al, 2019 ; Herrera, 2021 ; Gurung and Li, 2022 ), autophagy ( Tang et al, 2020 ), and EMT ( Chen et al, 2022b ) would result in degenerative hypertrophy, fibrosis, atrophy, and neoplasm ( Ryu et al, 2019 ; Pinto et al, 2021 ) comorbid conditions ( Charles and Ferris, 2020 ).…”

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

“…Vasoreactivity in isolated mouse MA and renal interlobar arteries (ILA) was tested using vascular myography and in AA, efferent arterioles (EA), and VR using microvascular perfusion as described previously. 29,30…”

Hypoxia-induced signaling in the cardiovascular system: pathogenesis and therapeutic targets

“…[586][587][588][589] In the presence of low oxygen levels (hypoxia), NO donors have the ability to modulate the hypoxic pathway, facilitating cellular adaptation and mitigating the adverse effects of hypoxia. 588,590 Consequently, the utilization of NO donors as a therapeutic approach has been implemented in the field of cardiovascular medicine to enhance cardiac blood flow and alleviate symptoms associated with angina. Medications based on NO donors can be classified into different categories.…”