Excessive salt consumption is one of the hypertension and kidney disease factors, while telmisartan is one of antihypertensive drugs used in the therapy. Telmisartan not only blocks angiotensin receptor which leads to the decrease of blood pressure, but also activates peroxisome proliferator activated receptor gamma (PPAR-γ) and inhibits transforming growth expression factor of beta-1 (TGFβ-1). Whether telmisartan decreases the kidney collagen volume fraction of excessive NaCl-induced Wistar rats are studied in this experiment.

Twenty five male Wistars 2.5-3 months of age and 100-150 g BW rats were used in this research. They were grouped into 5, each consists of 5 rats. Group I (G I) as first negative control did not receive NaCl and telmisartan. G II as second negative control received NaCl but not telmisartan. G III, IV and V received NaCl and telmisartan 3, 6 and 12 mg/kg BW. The treatments were given every day within 8 weeks. At the day of 56 all rats were sacrificed by mean of neck dislocation and operated to take the kidney. The collagen was stained by picrosirius red staining. Data were expressed as mean ± standard deviation. They were analyzed by parametric test (analysis of variance-ANOVA and paired samples t-test) or nonparametric test (Kruskal-Wallis). A value of p<0.05 was considered statistically significant.

The results showed that intraglomerular and extraglomerular collagen volume fraction were lower in telmisartan-treated Wistar rats group than negative control group (0.05

Keywords: NaCl, Telmisartan, TGF-β, Collagen

The increase of NCD prevalence such as hypertension, diabetes mellitus (DM) and obesity causes the raise of chronic kidney disease (CKD) prevalence about 8% per year. CKD is recently the main and global health problem that the mechanism of preventing and inhibiting the progression of the end stage renal disease (ESRD) is still researched. The primer cause of ESRD is DM 50%, arterial hypertension  27%,  glomerulonefritis  13%  and other cause cause 10% [2].

Primer or essential hypertension is the main society health problem. In 2005, approximately 1 billion people (14%) globally had hypertension. Hypertension is the main risk factor for cardiovascular, cerebrovascular and kidney diseases that related to the fibrosis occurrence in several organs, such as heart, kidney, liver and cardiovascular [3,4].

The increase of blood pressures usually is caused by combination of many factors. Epidemiologic proofs show that genetic, stress and environmental factor play a role for developmental hypertension [5], but excessive sodium chloride (NaCl) consumption is the main factor which induces hypertension and mainly causes cardiovascular and kidney disease globally [6]. The mechanism of blood pressure increases that induced by excessive NaCl is still incomprehensive, but may be related to kidney disability to excrete NaCl in high concentration [7]. The connection between excessive NaCl and blood pressure is still incomprehensive as well and in fact, it is denied by particular social community. Currently many researches focus on the mechanism of kidney destruction by NaCl, sympathetic nerve activity (SNA) increased by baroreflex mechanism and collagen deposition [3].

According to the previous research on animal model, it showed that 8% sodium chloride induced hypertension on spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats (NWKYs) [8]. The induction mechanism is suspected through the activation of angiotensin II by sodium in the way of aldosterone → endogenous oabain (EO) [9]. Angiotensin II stimulates vasoconstriction and induces adrenal gland to secrete aldosterone. Furthermore, aldosterone stimulates distal tubulus to reabsorb sodium and water [10,11]. Moreover, angiotensin II induces the change of fibroblast to miofibroblast by pathway of transforming growth factor-beta1 (TGF-β1). Miofibroblast produces exaggerated extracelluer matrix (ECM), therefore, ECM accumulates in tubulointerstitial area [12].

One of many antihypertensive drugs which widely used is angiotensin receptor blockers (ARBs) such as telmisartan. Telmisartan not only blocks angiotensin receptor, but also plays a role as agonist partial peroxisome proliferator activated receptor-γ (PPAR-γ), so that it activates PPAR-γ [13,14]. The activation causes PPAR-γ forms heterodimer with retinoid X receptors (RXRs) so that co-repressor is formed that can inhibit gene expression of TGF-β1[15].

Twenty five male Wistar 2.5-3 months of age and 100-150 g BW rats were used in this experiment. They were maintained in individual pen and given feed pellet and drinking water adequately. Placed in room temperature 20-24°C, dark-bright cycle for 12 h. Before doing treatment, animal model was acclimatized for maximal seven days. They were grouped into 5, each consists of rats. Group I (G I) as first negative control did not receive NaCl and telmisartan. G II as second negative control received NaCl but not telmisartan. G III, IV and V received NaCl and telmisartan 3, 6 and 12 mg/kg BW. The treatments were given every day for 8 weeks. At the day of 56 all rats were sacrificed by dislocating their necks and operating to take the kidney [16-20].

40 telmisartan was crushed mortally and then add water until 40 mL. Its suspension was taken by syringe suitable to rat’s dosages that have been determined to be entered directly to the rats’ stomach.

Collagen was stained by picrosirius red staining. BMP-7 protein expression and collagen fraction volume was determined by measuring the area of stained tissue within a given field. The area stained was calculated by imageJ software as percentage of the total area within a field [8,21,22].

STATICTICAL ANALYSIS

1.    World Health Organisation (WHO) (2010) Global status report on non-communicable diseases. Geneva, Switzerland.

2.    Baltatzi M, Ch S, Hatzitolios A (2011) Role of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in hypertension of chronic kidney disease and renoprotection. Hippokratia 15: 27-32.

3.    Blaustein MP, Leenen FHH, Chen L, Golovina VA, Hamlyn JM, et al. (2012) How NaCl raises blood pressure: A new paradigm for the pathogenesis of salt-dependent hypertension. Am J Physiol Heart Circ Physiol 302: H1031-H1049.

4.    Cox N, Pilling D, Gomer RH (2012) NaCl potentiates human fibrocyte differentiation. PLoS One 7: 1-9.

5.    Beevers G, Lip GYH, O’Brien E (2001) ABC of hypertension: “The pathophysiology of hypertension”. BMJ 322: 912-916.

6.    He FJ, Jenner KH, MacGregor GA, Avenue G (2012) Telmisartan exerts renoprotective actions via peroxisome. Hypertension 59: 308-316.

7.    Meneton P, Jeunemaitre X, Wardener HEDE, Macgregor GA (2005) Links between dietary salt intake, renal salt handling, blood pressure and cardiovascular diseases. Physiol Rev 86: 679-715.

8.    Yu HCM, Burrell LM, Black MJ, Wu LL, Dilley RJ (1998) Salt induces myocardial and renal fibrosis in normotensive and hypertensive rats. Circulation 98: 2621-2628.

9.    Leenen FHH (2010) The central role of the brain aldosterone – “ouabain” pathway in salt-sensitive hypertension. BBA Mol Basis Dis 1802: 1132-1139.

10.  Jöhren O, Dendorfer A, Dominiak P (2004) Cardiovascular and renal function of angiotensin II type-2 receptors. Cardiovasc Res 62: 460-467.

11.  Starr C, McMillan B (2012) Human Biology. 9^th Edn. Brooks/Cole Cengage Learning, Canada.

12.  Mezzano SA, Ruiz-Ortega M, Egido J (2001) Angiotensin II and renal fibrosis. Hypertension 38: 635-638.

13.  Chambers S, Schachter M, Morrell J, Gaw A, Kirby M (2008) Telmisartan an effective anti-hypertensive for 24 h blood pressure control. Drugs in Context 4: 1-14.

14.  Funao K, Matsuyama M, Kawahito Y, Sano H, Chargui J (2009) Telmisartan as a peroxisome proliferator-activated receptor - Á ligand is a new target in the treatment of human renal cell carcinoma. Mol Med Rep 2: 193-198.

15.  Rotman N, Wahli W (2010) PPAR modulation of kinase-linked receptor signaling in physiology and disease. Physiology 25: 176-185.

16.  Xu L, Liu Y (2013) Administration of telmisartan reduced systolic blood pressure and oxidative stress probably through the activation of PI3K/Akt/eNOS pathway and NO release in spontaneously hypertensive rats. Physiol Res 62: 351-359.

17.  Younis F, Stern N, Limor R, Oron Y, Zangen S (2010) Telmisartan ameliorates hyperglycemia and metabolic profile in non-obese Cohen-Rosenthal diabetic hypertensive rats via peroxisome proliferator activator receptor-γ activation. Metabolism 59: 1200-1209.

18.  Matsumura T, Kinoshita H, Ishii N, Fukuda K, Motoshima H (2011) Telmisartan exerts anti-atherosclerotic effects by activating in macrophages. Arterioscler Thromb Vasc Biol 31: 1268-1275.

19.  Liu W, Wang W, Song SW, Gu XF, Ma XJ (2011) Synergism of telmisartan and amlodipine on blood pressure reduction and cardiorenal protection in hypertensive rats. J Cardiovasc Pharmacol 57: 308-316.

20.  Jawi IM, Yasa IWPS, Suprapta DN, Mahendra AN (2012) Anti-hypertensive effect and eNOS expressions in NaCl-induced hypertensive rats treated with purple sweet potato. Univ J Med Dent 1: 102-107.

21.  Lync MJ, Raphael SS, Mellor LD, Spare PD, Inwood MJH, et al. (1969) Medical Laboratory Technology and Clinical Pathology. W.B. Saunders Company, United States of America (USA).

22.  Fatchiyah AEL, Widyarti S, Rahayu S (2011) Biologi Molekuler "Prinsip Dasar Analisis". Erlangga, Jakarta.

23.  Shang QH, Min XQ, Liu C, Mao WH, Shang QH (2012) Effects of high salt diet on arterial remodelling and the intervention of telmisartan in wistar rats. Heart 98: E1-E319.