Tempol or candesartan prevents high-fat diet-induced hypertension and renal damage in spontaneously hypertensive rats.
BACKGROUND
Obesity has been strongly associated with the development and aggravation of hypertension and chronic kidney disease. To date, the systemic renin-angiotensin system (RAS) has been known to involve in obesity-induced tissue damage and hypertension. However, the intrarenal mechanism whereby obesity induces and aggravates hypertension and renal disease remains poorly understood. Therefore, we investigated the role of intrarenal RAS and oxidative stress in diet-induced hypertension and renal inflammation in spontaneously hypertensive rats (SHR) fed a high-fat diet.


METHODS
Male SHR and Wistar-Kyoto rats (WKY) were divided into eight groups: normal-fat diet-fed WKY (WKY-NF), high-fat diet-fed WKY (WKY-HF), high-fat diet-fed tempol-treated WKY (WKY-HF/T), high-fat diet-fed candesartan-treated WKY (WKY-HF/C), normal-fat diet-fed SHR (SHR-NF), high-fat diet-fed SHR (SHR-HF), high-fat diet-fed tempol-treated SHR (SHR-HF/T) and high-fat diet-fed candesartan-treated SHR (SHR-HF/C). After 12 weeks of treatment, haemodynamic measurements and histological assessment of the kidney were performed.


RESULTS
At the end of week 12, the high-fat fed SHR gained more body weight, their systolic blood pressure was further elevated and glucose intolerance induced. There was no significant difference in the insulin resistance index, serum lipid profile, plasma renin activity and serum aldosterone levels according to diet. However, the high-fat diet resulted in increases in immunohistochemical stains of renin and angiotensin II in the kidney. The real-time PCR also demonstrated significant increases in mRNA levels of renin, angiotensinogen and angiotensin-converting enzyme in the kidney, reflecting enhanced activation of the intrarenal RAS, which findings were also shown by Western blot analysis for renin and angiotensin II type 1 receptor. The expression of ED-1, osteopontin and TGF-beta1 in the renal cortex were prominently enhanced in the SHR-HF group with the increased intrarenal lipid concentrations and oxidative stress. Administration of tempol or candesartan in the high-fat diet-induced SHR inhibited the elevation of the systolic blood pressure, intrarenal lipid concentrations, oxidative stress and the degree of renal inflammation to the levels of, or more than, the SHR-NF with no differences in the body weight and periepididymal fat weight, compared to those in the SHR-HF group without such treatment.


CONCLUSIONS
Our study suggests that a high-fat diet induces fatty kidneys, aggravation of blood pressure and renal inflammation in the SHR. Blockade of oxidative stress by tempol or of RAS by candesartan ameliorates the increase in blood pressure and renal inflammation and improves intrarenal lipid accumulation. Therefore, antioxidants or angiotensin receptor blockers can prevent diet-induced hypertension and renal inflammation in hypertensive rats.
Chung
Sungjin
S
Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Park
Cheol Whee
CW
Shin
Seok Joon
SJ
Lim
Ji Hee
JH
Chung
Hyun Wha
HW
Youn
Dong-Ye
DY
Kim
Hyung Wook
HW
Kim
Byung Soo
BS
Lee
Jeong-Hwa
JH
Kim
Gheun-Ho
GH
Chang
Yoon Sik
YS
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D003497:Cyclic N-Oxides / Q000627:therapeutic use*; D004041:Dietary Fats / Q000008:administration & dosage; D006973:Hypertension / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D009765:Obesity / Q000150:complications / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013113:Spin Labels; D013777:Tetrazoles / Q000627:therapeutic use*
D000959:Antihypertensive Agents; D000975:Antioxidants; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D003497:Cyclic N-Oxides; D004041:Dietary Fats; D013113:Spin Labels; D013777:Tetrazoles; C081643:candesartan; C001803:tempol