SASARAN AKSI VITAMIN D PADA SISTEM RENIN ANGIOTENSIN-ALDOSTERON DALAM PENGATURAN TEKANAN DARAH SISTOLIK

Dessy Hermawan, Ns., M.Kes, Prof. dr. Sri Kadarsih Soejono, MSc, Ph.D.

2013 | Disertasi | S3 Kedokteran Umum

Mekanisme pembentukan renin di ginjal kemungkinan mirip dengan pembentukan prostaglandin yang terjadi di sel kanker. Beberapa kesamaan tersebut karena keduanya menggunakan COX-2 sebagai katalisator sintesis asam arakidonat menjadi prostaglandin dan memiliki reseptor prostaglandin pada sel targetnya. Mekanisme ini sangat menarik dan menimbulkan pertanyaan. Apakah mungkin jika mekanisme penghambatan COX-2 oleh vitamin D pada sel kanker dapat diterapkan juga pada penghambatan COX-2 di sel macula densa ginjal? Pertanyaaan inilah yang menarik penulis untuk meneliti lebih jauh tentang pengaruh vitamin D dalam penghambatan sekresi renin, baik melalui jalur down stream cAMP, yaitu dengan penekanan langsung ke gen yang memproduksi renin, maupun melalui jalur up stream cAMP, yaitu dengan penghambatan COX-2 di sel macula densa ginjal? Adapun tujuan penelitian ini adalah untuk mengkaji sasaran aksi vitamin D pada sistem renin angiotensin-aldosteron dalam pengaturan tekanan darah, terutama untuk mempelajari penghambatan vitamin D melalui jalur up stream cAMP. Subyek dalam penelitian ini adalah Rattus norvegicus jantan yang setelah diadaptasikan dibagi dalam beberapa kelompok, yang masing-masing mendapat asupan vitamin D berbeda-beda tanpa dan dengan tambahan teofilin serta mendapatkan tambahan indomethacine. Kemudian subyek diletakkan dalam kandang gelap dan diberi pakan tanpa vitamin D selama 7 hari. Kemudian dipindahkan dalam kandang terang dan diberi tambahan vitamin D berbagai dosis selama 4 hari. Adapun variabel yang diukur dalam penelitian ini adalah kadar 1,25(OH)2D3 darah, ekspresi COX-2 di sel macula densa, kadar cAMP sel ginjal, kadar renin darah dan tekanan darah sistolik/TDS. Dari hasil didapatkan bahwa semakin turun kadar vitamin D dalam darah, maka TDSnya mengalami peningkatan, sebaliknya peningkatan kadar vitamin D dalam darah akan diikuti dengan penurunan TDS. Pemberian vitamin D 0,5 μg/Kg BB/hari selama 4 hari mampu menurunkan ekspresi COX-2 di sel macula densa secara bermakna, sehingga kadar renin darah dan TDSnya tidak mengalami peningkatan. Pada variabel yang lain, vitamin D dosis 0,125 μg/Kg BB/hari selama 4 hari mampu menurunkan kadar cAMP sel ginjal, kadar renin darah dan TDS secara bermakna. Pemberian teofilin juga mampu mengakumulasi cAMP sel ginjal, namun jika diberikan bersama vitamin D, maka akumulasi cAMP di sel ginjal tidak terjadi, sehingga kadar renin dan TDS tidak mengalami peningkatan. Pemberian indomethacine mampu menurunkan ekspresi COX-2, namun lebih kuat efek penekanan COX-2 yang dilakukan oleh vitamin D 0,5 μg/Kg BB/hari. Berdasarkan hasil ini dapat ditarik kesimpulan bahwa vitamin D mampu menurunkan kadar renin darah juga melalui jalur up stream cAMP, yaitu dengan menekan ekspresi COX-2 di sel macula densa, kadar vitamin D dalam darah juga berkorelasi dengan TDS, vitamin D mampu menurunkan kadar cAMP sel ginjal dengan atau tanpa pemberian bersama teofilin dan vitamin D mampu menurunkan tekanan darah sistolik.

Mechanism of renin production in the kidney is likely to be similar to that of prostaglandins that occur in cancer cells. The reason for such similarities is that both use COX-2 as synthetic catalyst from arachidonic acid into prostaglandins and both have prostaglandin receptors in their target cells. It is an interesting mechanism that spurs the following question: Is it possible that the mechanism of COX-2 inhibition by vitamin D in cancer cells can also be applied to the COX-2 inhibition in kidney macula densa cells? It is precisely this question that attracted the author to further examine the effect of vitamin D on the inhibited renin secretion, both through downstream cAMP lines, that is, by directly pressing the renin-producing genes and trough upstream cAMP channel, i.e., by inhibiting COX-2 in kidney macula densa cells. This study aims to examine the target of vitamin D action on the renin-angiotensin-aldosterone system in regulating blood pressure, especially to study the inhibition of vitamin D through upstream cAMP lines. The subjects studied were male Rattus norvegicus. They were, after being adapted, divided into several groups, each of which received varying intake of vitamin D with and without additional theophylline and indomethacine. The subjects were subsequently placed in dark cages and fed without vitamin D for 7 days. They were then moved into the lighted cage and were given various doses of supplemental vitamin D for 4 days. The variables measured is the blood level of 1,25(OH)2D3, COX-2 expression in the macula densa cells, renal cell cAMP levels, blood renin levels and systolic blood pressure /SBP The results indicate that the lower the blood levels of vitamin D, the higher the SBP will be; on the contrary, increased blood levels of vitamin D will be followed by a decrease in SBP. Administered vitamin D of 0.5 μg /kg bw/ day for 4 days may significantly reduce the expression of COX-2 in the macula densa cells was, thus that the blood levels of renin and the SBP did not increase. In other variables, vitamin D of 0,125 μg / kg bw / day for 4 days can reduce renal cell cAMP levels, blood renin and SBP levels significantly. The administered theophylline may also accumulate cAMP of kidney cells, but when given with vitamin D, the accumulation of cAMP in kidney cells does not occur, thus the levels of renin and SBP did not increase. While the administered indomethacine may reduce the expression of COX-2, the effect of COX-2 suppression by vitamin D of 0,5 μg/Kg bw/day is stronger. From the results it is concluded that vitamin D may also reduce the blood level of renin through upstream cAMP line, that is by suppressing the COX-2 expression in cell macula densa. The blood level of vitamin D was also correlated with SBP. Vitamin D may reduce cAMP level in renal cells with or without additional theophylline and may also lower the systolic blood pressure.

Kata Kunci : Vitamin D, Renin, COX-2, cAMP dan TDS