CHAPTER I INTRODUCTION. Nowadays chronic kidney disease (CKD) becomes one. of the most common diseases found in the population.

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1 CHAPTER I INTRODUCTION I.1 Background Nowadays chronic kidney disease (CKD) becomes one of the most common diseases found in the population. Based on community survey that is held by PERNEFRI (Perhimpunan Nefrologi Indonesia) on 2012, about 12,5% population in Indonesia has suffered from reduced kidney function. From this survey, it assumed that more than 25 million of population has reduced kidney function (Pernefri, 2012). CKD become burden for the global public health because of its prevalence and consequence of the disease, such as cardiovascular disease, end stage renal disease, and also premature death(sah & Ching, 2002). CKD characterized by appearance of vascular sclerosis, tubulointerstitial fibrosis and glomerulosclerosis. It is accompanied by infiltration of macrophage and T cells. The factors that influencing the remodeling and tissue damage in progression of disease remain not totally understandable. Thus, 1

2 2 comprehensive understanding of pathomechanism of CKD still remains unknown (Ryu, 2012). Many Previous studies had tried to elucidate the cause of glomerulosclerosis. Many studies showed that there are several mechanisms related to glomerulosclerosis. Ryu, (2012) studied about the role of TNF alpha on progressive glomerulosclerosis in Alport Nephropathy. Other studies showed an increase of sclerosis in glomerulus due to effect of Plasminogen Activating Inhibitor 1( PAI-1) (Fogo, 2007). Toll like receptors (TLRs) are innate immune receptors expressed by immune cells. TLRs recognize various pathogen-associated dangers and promote activation of leukocyte. There are 10 human TLR family members, each of them has functional properties and distinct ligands (Banas et al., 2008). Ligands of TLRs include exogenous component from microbial such as lipoproteins and peptidoglicans (TLR1,-2,-6), viral unmethylated cytosine-guanosin dinucleotide (CpG)-DNA (TLR9), viral RNA (TLR3), and LPS (TLR4). It also binds with endogenous molecules such as heat shock protein and extracellular matrix molecules (Anders & Schlondorff, 2004). There are many studies about the contribution of TLRs in the pathogenesis of the renal

3 3 disease. TLR4 was positively found in podocytes with the innate immune system to mediate glomerular injury in the cyroglobulinemic membranoproliferative glomerulonephritis (MPGN) (Banas et al., 2008). Interestingly, recent studies showed that TLR4 involved during fibrogenesis. It is known that TLR4 can enhance TGFβ signaling and myofibroblast activation in the model of hepatic fibrogenesis (Seki et al., 2007). Another study demonstrate that TLR4 was enhance during progressive renal disease and promote fibrosis in tubular. TLR4 was shown induced TGFβ signaling to mediate fibrosis. Then, TECs and myofibroblast induced a profibrogenic response due to TGFβ stimulation (Pulskens et al., 2010). In renal fibrosis, endogenous TLR ligands such as hyaloran, heparan sulfate, and fibronectin EDA were exposed by TLR4 on macrophage due to increase matrix turnover. Immune cells and intrinsic renal cell that response to activation of TLR will promote the secretion of cytokines and chemokine that will add additional leukocyte recruitment in kidney supporting the interstitial fibrosis and interstitial inflammation (Anders & Schlondorff, 2004).

4 4 Degree of glomerulosclerosis and proteinuria is shown to be decrease when TGFβ is blocked (Zhou et al., 2008) From the previous study mention above, it strongly supports that TLR4 and glomerulosclerosis has correlation. Until now there is no research has been conducted yet related to this matter. I.2 Research question Based from the background explained before, we can formulate the problem as: 1. Is there any increase of glomerulosclerosis after 5/6 subtotal nephrectomy? 2. Is there any increase in the TLR4 expression after 5/6 subtotal nephrectomy? 3. Does glomerulosclerosis correlate with expression of TLR4? I.3 Research Objectives General objectives To find out whether expression of TLR4 are correlate with degree of glomerulosclerosis as consequence of kidney failure induction after 5/6 subtotal nephrectomy in mice.

5 5 Specific objectives 1. To investigate if there is an increase of glomerulosclerosis after 5/6 subtotal nephrectomy. 2. To investigate if there is alteration in expression of TLR4 after 5/6 subtotal nephrectomy. 3. To investigate the correlation between glomerulosclerosis and expression of TLR4 after 5/6 subtotal nephrectomy. I.4 Research authenticity The previous studies reveals that several studies have been conducted related to expression of TLR4 and chronic kidney disease. Banas et al.,(2008) studied about TLR4 expressed in podocyte and upregulated in MPGN. The study only inform that TLR4 is highly expressed in podocyte during inflammation. Kasco et al.,(2015) also conducted study about TLR4. This study is similar with the researcher s study but, the method is different. The study was using immunohistochemistry to assess TLR4 expression, while the researcher s study is using RT-PCR to determine TLR4 expression and it assessed TLR4 expression only in

6 6 week 12, while the researcher s study assessed TLR4 in week 1 and week 4. Pulskens et al.,(2010) studied about TLR4 promotes fibrosis in tubular damage. It did not study about TLR4 related to the glomerulosclerosis. In conclusion, this study has some similarity with other studies, but has not been specifically done by other researchers. It is also not a plagiarism from previous studies. I.5 Research benefit 1. For Author The expected benefit for the author is to improve knowledge about chronic kidney disease, particularly the correlation between expression of TLR4 and degree of glomerulosclerosis in the process of kidney fibrosis and also to fulfill the requirement for the attainment of bachelor of medical degree in Faculty of Medicine in Gadjah Mada University. 2. For education The benefit for education is to unveiling the correlation serexpression of TLR4 and glomerulosclerosis in kidney fibrosis process so can give inspiration to other researchers to investigate

7 7 further more about the correlation between those variables, chronic kidney failure and other accompanying disorders. 3. For clinician The expected benefit from this research is to help clinician in diagnosing the chronic kidney disease based on blood analysis of TLR4 expression. 4. For community Benefits for the community is to provide further understanding of chronic kidney disease that often appears in public. So people will become more aware to maintain healthy kidney and able to take preventive action against kidney disease.