Endothelial dysfunction and oxidative stress in polycystic kidney disease

Abstract

Cardiovascular disease (CVD) is the leading cause of premature mortality in ADPKD patients. The aim was to identify potential serum biomarkers associated with the severity of ADPKD. Serum samples from a homogenous group of 61 HALT study A ADPKD patients [early disease group with estimated glomerular filtration rate (eGFR) >60 ml·min(-1)·1.73 m(-2)] were compared with samples from 49 patients from the HALT study B group with moderately advanced disease (eGFR 25-60 ml·min(-1)·1.73 m(-2)). Targeted tandem-mass spectrometry analysis of markers of endothelial dysfunction and oxidative stress was performed and correlated with eGFR and total kidney volume normalized to the body surface area (TKV/BSA). ADPKD patients with eGFR >60 ml·min(-1)·1.73 m(-2) showed higher levels of CVD risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA), homocysteine, and S-adenosylhomocysteine (SAH) compared with the healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, SDMA, homocysteine, and SAH remained negatively correlated with eGFR. Resulting cellular methylation power [S-adenosylmethionine (SAM)/SAH ratio] correlated with the reduction of renal function and increase in TKV. Concentrations of prostaglandins (PGs), including oxidative stress marker 8-isoprostane, as well as PGF2α, PGD₂, and PGE₂, were markedly elevated in patients with ADPKD compared with healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, increased PGD₂ and PGF₂α were associated with reduced eGFR, whereas 8-isoprostane and again PGF₂α were associated with an increase in TKV/BSA. Endothelial dysfunction and oxidative stress are evident early in ADPKD patients, even in those with preserved kidney function. The identified pathways may provide potential therapeutic targets for slowing down the disease progression.

Keywords: ADPKD; NO pathway; biomarkers; endothelial dysfunction; oxidative stress.

Fig. 1.

Differences in asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) concentrations in serum of adult autosomal dominant polycystic kidney disease (ADPKD) patients with higher total kidney volume (TKV) but preserved estimated glomerular filtration rate (eGFR) >60 ml·min⁻¹·1.73 m⁻² (A) and comparison between healthy subjects and ADPKD patients with preserved and moderately reduced eGFR (B). Values are means ± SD. Significance levels: *P < 0.05, **P < 0.01, ***P < 0.001 vs. TKV < 800 ml (A) and vs. healthy subjects (B). For significance levels between the ADPKD patients with preserved and moderately reduced eGFR, please refer to Table 4.

Fig. 2.

Changes in methylation cycle intermediates and cardiovascular disease (CVD) risk markers homocysteine (Hcy) and S-adenosylhomocysteine (SAH) in serum of ADPKD adults with increasing TKV but preserved eGFR >60 ml·min⁻¹·1.73 m⁻² (A) and comparison between healthy subjects and ADPKD patients with preserved and moderately reduced eGFR (B). Values are means ± SD. Significance levels: *P < 0.05, **P < 0.01, ***P < 0.001 vs. TKV < 800 ml (A) and vs. healthy subjects (B). S-adenosylmethionine (SAM) and SAH are presented in nM, Hcy and methionine (Met) in μM. For significance levels between the ADPKD patients with preserved and moderately reduced eGFR, please refer to Table 4.

Fig. 3.

Changes in concentrations of prostaglandins in serum of adult ADPKD patients with increasing TKV but preserved eGFR >60 ml·min⁻¹·1.73 m⁻² (A) and comparison between healthy subjects and ADPKD patients with preserved and moderately reduced eGFR (B). Values are means ± SD. To facilitate visual comparison, error bars are not completely shown. The mean ± SD for PGD₂ was 4,510 ± 3,483 pg/ml. Significance levels: *P < 0.05, ***P < 0.001 vs. TKV < 800 ml (A) and vs. healthy subjects (B). For significance levels between ADPKD patients with preserved and moderately reduced eGFR, please refer to Table 4.

Fig. 4.

Proposed mechanistic hypothesis based on the published data and the results of the present study in patients with ADPKD. A vicious cycle is created, in which renal cysts activate the renin-angiotensin-aldosterone system (RAAS). The resulting increase in ANG II leads to 1) increased levels of endothelial nitric oxide synthase (NOS) inhibitor ADMA and SDMA that deplete nitric oxide (NO); 2) increased Hcy and SAH levels within the methylation pathway and lower SAM/SAH ratio, indicating diminished methylation capacity; and 3) increased metabolism of arachidonic acid (AA), leading to generation of proinflammatory and oxidative stress, accelerating prostaglandins. Oxidative stress, vascular inflammation, and endothelial dysfunction in turn augment the cyst compression of renal vasculature and activate RAAS.