Intermittent hypoxia exacerbates increased blood pressure in rats with chronic kidney disease

Abstract

Kidney injury and sleep apnea (SA) are independent risk factors for hypertension. Exposing rats to intermittent hypoxia (IH) to simulate SA increases blood pressure whereas adenine feeding causes persistent kidney damage to model chronic kidney disease (CKD). We hypothesized that exposing CKD rats to IH would exacerbate the development of hypertension and renal failure. Male Sprague-Dawley rats were fed a 0.2% adenine diet or control diet (Control) until blood urea nitrogen was >120 mg/dl in adenine-fed rats (14 ± 4 days, mean ± SE). After 2 wk of recovery on normal chow, rats were exposed to IH (20 exposures/h of 5% O2-5% CO2 7 h/day) or control conditions (Air) for 6 wk. Mean arterial pressure (MAP) was monitored with telemeters, and plasma and urine samples were collected weekly to calculate creatinine clearance as an index of glomerular filtration rate (GFR). Prior to IH, adenine-fed rats had higher blood pressure than rats on control diet. IH treatment increased MAP in both groups, and after 6 wk, MAP levels in the CKD/IH rats were greater than those in the CKD/Air and Control/IH rats. MAP levels in the Control/Air rats were lower than those in the other three groups. Kidney histology revealed crystalline deposits, tubule dilation, and interstitial fibrosis in both CKD groups. IH caused no additional kidney damage. Plasma creatinine was similarly increased in both CKD groups throughout whereas IH alone increased plasma creatinine. IH increases blood pressure further in CKD rats without augmenting declines in GFR but appears to impair GFR in healthy rats. We speculate that treating SA might decrease hypertension development in CKD patients and protect renal function in SA patients.

A dual blocker of endothelin A/B receptors mitigates hypertension but not renal dysfunction in a rat model of chronic kidney disease and sleep apnea

“…Hypertension is a leading risk factor for the initiation and progression of CKD as well as a consequence of CKD. Using adenine oral administration to cause CKD in rats, we previously demonstrated that CKD and IH additively elevate blood pressure, but IH does not enhance adenine-induced renal fibrosis, inflammation, and decline of kidney function (31). In the same study, pre-pro-ET-1 mRNA levels were increased in the renal cortex and medulla of CKD rats, whereas IH did not further enhance ET-1 expression (31).…”

“…CKD model induction and prevention assessment protocol. CKD was induced by feeding rats 0.2% adenine (Sigma-Aldrich) mixed in Nutra-gel (Bio Serv) for 2 wk (31), which is equivalent to a dose of 40 g•rat Ϫ1 •day Ϫ1 . Rats in CKD and control groups assigned to concurrent macitentan received 30 mg•kg Ϫ1 •day Ϫ1 in the same food.…”

“…IH exposure. After 2 wk of recovery on control or macitentancontaining food, rats in the IH groups were exposed to 20 hypoxic episodes/h (90 s of air followed by 90 s of progressive hypoxia down to 5% inhaled O2 to model moderate sleep apnea) during their sleep period for 6 wk as previously described (3,4,24,31). CO2 was added during hypoxia to prevent hypocapnia during the hypoxia-induced hyperventilation (34).…”

“…However, the mechanisms linking OSA with cardiovascular diseases and CKD are still unclear. This study used an experimental animal model developed to mimic the cardiovascular-hemodynamic changes in OSA (5,28), a model previously validated in our laboratory (8,31).…”

“…Using adenine oral administration to cause CKD in rats, we previously demonstrated that CKD and IH additively elevate blood pressure, but IH does not enhance adenine-induced renal fibrosis, inflammation, and decline of kidney function (31). In the same study, pre-pro-ET-1 mRNA levels were increased in the renal cortex and medulla of CKD rats, whereas IH did not further enhance ET-1 expression (31). In patients with CKD, COOH-terminal pro-ET-1 peptide plasma levels inversely correlate with estimated glomerular filtration rate (eGFR) (15).…”