林水龍教授

腎臟與高血壓

研究方向

我們的主要興趣在研究腎臟相關疾病，老化與併發症的病理機轉及其治療。台灣的慢性腎病病患需要透析治療的盛行率與發生率都高居世界第一，各種急性腎損傷或急性腎病的巨大醫療支出與併發症也是全球的重要課題。我們有這個必要，也有這種優勢可以在這領域深入研究。

在整合病患的臨床資料後，我們利用動物實驗以證實其因果關係並尋找新穎治療。本實驗室主要的研究工具為基因改造或基因轉殖鼠，利用reporter mice或特定腎臟細胞之特定基因於特定時間進行基因剔除以觀察其對於腎臟再生/修復/纖維化/老化/腫瘤，腎臟病合併症，透析造成腹膜炎/腹膜硬化的影響，以及研發次世代的腎臟替代療法。研究的細胞包括腎臟血管周邊細胞(pericytes)，腎臟小管上皮細胞(renal tubular epithelial cells)，腎小球足細胞(podocytes)，腹膜上皮細胞(mesothelial cells)，腹膜下纖維母細胞(submesothelial fibroblasts)，巨嗜細胞(macrophages)，淋巴球細胞(lymphocytes)，血管內皮細胞(endothelial cells)等。有持續關注的分子包括促紅血球生成素(erythropoietin)，低氧誘發因子(hypoxia-inducible factors), 甲基移轉酶(methyltransferase), 血管生成素(angiopoietin)，第二型血管張力素(angiotensin II)，荃固酮(aldosterone)，與galectin-3 (半乳糖凝集素-3)等。

研究主題

表基因調控腎臟血管周邊細胞。
腎臟細胞的交互作用在腎臟損傷與修護的角色。
腹膜細胞的交互作用在腹膜損傷與修護的角色。
慢性腎病相關的心血管疾病病理機轉與治療。
腎臟老化的機轉。
T淋巴球分化與功能。
次世代的腎臟替代療法。

實驗室技術

1. 基因改造鼠: Cre-loxP system, transgenic mice

2. 動物模式: organ fibrosis, peritonitis, acute kidney injury, bone marrow transplantation, parabiosis

3. 病毒載體技術: adenovirus, retrovirus, lentivirus

4. 細胞培養: kidney cells, bone marrow derived macrophages, endothelial cells, mesothelial cells, fibroblasts

5. 分子生物學: RNA, DNA, protein, epigenetic

6. 組織免疫學: immunohistochemistry, immunofluorescence

Publication list

Hsu YH, Lin SL* (2022, Feb). Exploring the kidney disease data of Taiwan, a country with the highest incidence and prevalence of treated ESKD worldwide - Hints for public health and policy initiative. J Formos Med Assoc, 121 Suppl 1:S1-S2.
Shih HM, Pan SY, Wu CJ, Chou YH, Chen CY, Chang FC, Chen YT, Chiang WC, Tsai HC, Chen YM, Lin SL* (2021, Nov). Transforming growth factor-β1 decreases erythropoietin production through repressing hypoxia-inducible factor 2α in erythropoietin-producing cells. J Biomed Sci, 28(1):73.
Pan SY, Tsai PZ, Chou YH, Chang YT, Chang FC, Chiu YL, Chiang WC, Hsu T, Chen YM, Chu TS, Lin SL*. Kidney pericyte hypoxia-inducible factor regulates erythropoiesis but not kidney fibrosis. Kidney Int. 2021 Jun;99(6):1354-1368. doi: 10.1016/j.kint.2021.01.017. Epub 2021 Mar 31.
Pai CH, Lin SR, Liu CH, Pan SY, Hsu H, Chen YT, Yen CT, Yu IS, Wu HL, Lin SL*, Lin SW* (2020, Oct). Targeting fibroblast CD248 attenuates CCL17-expressing macrophages and tissue fibrosis. Sci Rep, 10(1):16772.
Chou YH, Pan SY, Shao YH, Shih HM, Wei SY, Lai CF, Chiang WC, Schrimpf C, Yang KC, Lai LC, Chen YM, Chu TS*, Lin SL* (2020, Sep). Methylation in pericytes after acute injury promotes chronic kidney disease. J Clin Invest, 130(9):4845-4857.
Chen YT, Hsu H, Lin CC, Pan SY, Liu SY, Wu CF, Tsai PZ, Liao CT, Cheng HT, Chiang WC, Chen YM, Chu TS, Lin SL (2020, Jan). Inflammatory macrophages switch to CCL17-expressing phenotype and promote peritoneal fibrosis. J Pathol, 250(1):55-66.
Chiang WC, Huang YC, Fu TI, Chen PM, Chang FC, Lai CF, Wu VC, Lin SL, Chen YM (2019, Feb). Angiopoietin 1 influences ischemic reperfusion renal injury via modulating endothelium survival and regeneration. Mol Med, 25(1):5.
Shih HM, Wu CJ, Lin SL (2018, Nov). Physiology and pathophysiology of renal erythropoietin-producing cells. J Formos Med Assoc, 117(11):955-963.
Lin YF, Lin SL, Huang TM, Yang SY, Lai TS, Chen L, Wu VC, Chu TS, Wu KD; National Taiwan University Hospital Study Group on Acute Renal Failure (NSARF) (2018, Oct). New-onset diabetes after acute kidney injury requiring dialysis. Diabetes Care, 41(10):2105-2110.
Shih YC, Chen CL, Zhang Y, Mellor RL, Kanter EM, Fang Y, Wang HC, Hung CT, Nong JY, Chen HJ, Lee TH, Tseng YS, Chen CN, Wu CC, Lin SL, Yamada KA, Nerbonne JM, Yang KC (2018, Apr). Endoplasmic reticulum protein TXNDC5 augments myocardial fibrosis by facilitating extracellular matrix protein folding and redox-sensitive cardiac fibroblast activation. Circ Res, 122(8):1062-1068.
Chou YH, Huang TM, Pan SY, Chang CH, Lai CF, Wu VC, Wu MS, Wu KD, Chu TS, Lin SL (2017, Apr). Renin-angiotensin system inhibitor is associated with lower risk of ensuing chronic kidney disease after functional recovery from acute kidney injury. Sci Rep 7:46518.
Pan SY, Chiang WC, Chen PM, Liu HH, Chou YH, Lai TS, Lai CF, Chiu YL, Lin WY, Chen YM, Chu TS, Lin SL (2017, Mar). restricted use of erythropoiesis-stimulating agent is safe and associated with deferred dialysis initiation in stage 5 chronic kidney disease. Sci Rep 7:44013
Cheng SY, Chou YH, Liao FL, Lin CC, Chang FC, Liu CH, Huang TM, Lai CF, Lin YF, Wu VC, Chu TS, Wu MS, Lin SL. (2016, Sep). Losartan reduces ensuing chronic kidney disease and mortality after acute kidney injury. Sci Rep 6:34265.
Chang YT, Yang CC, Pan SY, Chou YH, Chang FC, Lai CF, Tsai MH, Hsu HL, Lin CH, Chiang WC, Wu MS, Chu TS, Chen YM, Lin SL (2016, Feb). DNA methyltransferase inhibition restores erythropoietin production in fibrotic murine kidneys. J Clin Invest, 126(2):721-731.
Chen YT, Chang YT, Pan SY, Chou YH, Chang FC, Yeh PY, Liu YH, Chiang WC, Chen YM, Wu KD, Tsai TJ, Duffield JS, Lin SL (2014, Dec). Lineage tracing reveals distinctive fates for mesothelial cells and submesothelial fibroblasts during peritoneal injury in mice. J Am Soc Nephrol, 25: 2847–2858.
Chang FC, Chiang WC, Tsai MH, Chou YH, Pan SY, Chang YT, Yeh PY, Chen YT, Chiang CK, Chen YM, Chu TS, Wu KD, Lin SL (2014, Jun). Angiopoietin 2 Induced Arterial Stiffness in Chronic Kidney Disease. J Am Soc Nephrol, 25: 1198-1209.
Ren S, Johnson B, Kida Y, Ip C, Davidson KC, Lin SL, Kobayashi A, Lang RA, Hadjantonakis AK, Moon RT, Duffield JS (2013, Jan). LRP-6 is co-receptor for multiple fibrogenic signaling pathways in pericytes and myofibroblasts that are inhibited by DKK-1. Proc Natl Acad Sci USA, 110:1440-1445.
Wu CF, Chiang WC, Lai CF, Chang FC, Chen YT, Chou YH, Wu TH, Linn GR, Ling H, Wu KD, Tsai TJ, Chen YM, Duffield JS, Lin SL (2013, Jan). Transforming growth factor β stimulates profibrotic epithelial signaling to activate pericyte-myofibroblast transition in obstructive kidney fibrosis. Am J Pathol, 182: 118-131.
Chen YT, Chang FC, Wu CF, Chou YH, Hsu HL, Chiang WC, Chen YM, Wu KD, Tsai TJ, Duffield JS, Lin SL. (2011, Dec). Platelet-derived growth factor receptor signaling activates pericyte-myofibroblast transition in obstructive and post-ischemic kidney fibrosis. Kidney Int, 80(11):1170-81.
Lin SL, Chang FC, Schrimpf C, Chen YT, Wu CF, Wu VC, Chiang WC, Kuhnert F, Kuo C, Chen YM, Wu KD, Tsai TJ, Duffield JS. (2011, Feb). Targeting endothelium-pericyte crosstalk by inhibiting VEGF receptor signaling attenuates kidney microvascular rarefaction and fibrosis. Am J Pathol, 178(2): 911-923.
Lin SL, Li B, Rao S, Yeo EJ, Hudson TE, Nowlin BT, Pei H, Chen LJ, Zheng JJ, Carroll TJ, Pollard JW, McMahon AP, Lang RA, Duffield JS. (2010, Mar). Macrophage Wnt7b is critical for kidney repair and regeneration. Proc Natl Acad Sci USA, 107(9):4194-9.
Humphreys BD, Lin SL, Kobayashi A, Hudson TE, Nowlin BT, Bonventre JV, Valerius MT, McMahon AP, Duffield JS (2010, Jan). Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol, 176(1):85-97.
Castaño AP, Lin SL, Surowy T, Nowlin BT, Turlapati SA, Patel T, Singh A, Li S, Lupher Jr. ML, Duffield JS (2009, Nov). Serum amyloid P inhibits fibrosis through FcγR-dependent monocyte-macrophage regulation in vivo. Science Transl Med, 1, 5ra13.
Lin SL, Castaño AP, Nowlin BT, Lupher ML Jr, Duffield JS (2009, Nov). Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations. J Immunol , 183(10):6733-43.
Lin SL, Kisseleva T, Brenner DA, Duffield JS (2008, Dec). Pericytes and perivascular fibroblasts are the primary source of collagen producing cells in obstructive fibrosis of the kidney. Am J Pathol, 173(6):1617-1627.
Lin SL, Chen YM, Chiang WC, Wu KD, Tsai TJ (2008, Sep). Effect of pentoxifylline in addition to losartan on proteinuria and GFR in CKD: A 12-month randomized trial. Am J Kidney Dis,52(3):464-474.
Chen YM, Lin SL, Chiang WC, Wu KD and Tsai TJ (2006, Aug). Pentoxifylline ameliorates proteinuria via suppression of renal MCP-1 in subnephrotic primary glomerular diseases. Kidney Int, 69(8):1410-1415.
Lin SL, Chen RH, Chen YM, Chiang WC, Lai CF, Wu KD, Tsai TJ (2005, Sep). Pentoxifylline attenuates tubulointerstitial fibrosis by blocking Smad3/4-activated transcription and profibrogenic effects of connective tissue growth factor. J Am Soc Nephrol, 16,2702-2713.
Lin SL, Chen YM, Chien CT, Chiang WC, Tsai CC, Tsai TJ (2002, Dec). Pentoxifylline attenuated the renal disease progression in rats with remnant kidney. J Am Soc Nephrol, 13:2916-2929.

https://sites.google.com/g.ntu.edu.tw/linlabntu/home

https://instagram.com/ntu.kidney.physiol

Interests
Cross-talk between pericytes and endothelial cells/epithelial cells in progressive organ fibrosis
Cross-talk between mesohtelial cells and submesothelial fibroblasts in peritoneal injury
Multi-potent stem cells and stroma cells in tissue repair, focus on kidney and peritoneum
Inflammatory macrophages in organ fibrosis
Trophic macrophages in tissue repair and regeneration
Pathogenesis of cardiovascular disease in chronic kidney disease, focus on angiopoietin/Tie-2 system and trophic macrophages
Erythropoietin producing cells in normal and fibrosing kidneys

Laboratory Techniques
Genetically modified mice: Cre-loxP system, transgenic mice
Animal models: organ fibrosis (kidney, liver, peritoneum), glomerulonephritis, peritonitis, acute kidney injury, bone marrow transplantation
Virus-delivered targeting: adenovirus, retrovirus, lentivirus
Primary cell cultures: kidney cells, bone marrow derived macrophages
Molecular biology: RNA, DNA, protein
Tissue histopathology: immunohistochemistry, immunofluorescence

Publication list

Chen YT, Hsu H, Lin CC, Pan SY, Liu SY, Wu CF, Tsai PZ, Liao CT, Cheng HT, Chiang WC, Chen YM, Chu TS, Lin SL (2020, Jan). Inflammatory macrophages switch to CCL17-expressing phenotype and promote peritoneal fibrosis. J Pathol, 250(1):55-66.
Chiang WC, Huang YC, Fu TI, Chen PM, Chang FC, Lai CF, Wu VC, Lin SL, Chen YM (2019, Feb). Angiopoietin 1 influences ischemic reperfusion renal injury via modulating endothelium survival and regeneration. Mol Med, 25(1):5.
Shih HM, Wu CJ, Lin SL (2018, Nov). Physiology and pathophysiology of renal erythropoietin-producing cells. J Formos Med Assoc, 117(11):955-963.
Lin YF, Lin SL, Huang TM, Yang SY, Lai TS, Chen L, Wu VC, Chu TS, Wu KD; National Taiwan University Hospital Study Group on Acute Renal Failure (NSARF) (2018, Oct). New-onset diabetes after acute kidney injury requiring dialysis. Diabetes Care, 41(10):2105-2110.
Shih YC, Chen CL, Zhang Y, Mellor RL, Kanter EM, Fang Y, Wang HC, Hung CT, Nong JY, Chen HJ, Lee TH, Tseng YS, Chen CN, Wu CC, Lin SL, Yamada KA, Nerbonne JM, Yang KC (2018, Apr). Endoplasmic reticulum protein TXNDC5 augments myocardial fibrosis by facilitating extracellular matrix protein folding and redox-sensitive cardiac fibroblast activation. Circ Res, 122(8):1062-1068.
Chou YH, Huang TM, Pan SY, Chang CH, Lai CF, Wu VC, Wu MS, Wu KD, Chu TS, Lin SL (2017, Apr). Renin-angiotensin system inhibitor is associated with lower risk of ensuing chronic kidney disease after functional recovery from acute kidney injury. Sci Rep 7:46518.
Pan SY, Chiang WC, Chen PM, Liu HH, Chou YH, Lai TS, Lai CF, Chiu YL, Lin WY, Chen YM, Chu TS, Lin SL (2017, Mar). restricted use of erythropoiesis-stimulating agent is safe and associated with deferred dialysis initiation in stage 5 chronic kidney disease. Sci Rep 7:44013
Cheng SY, Chou YH, Liao FL, Lin CC, Chang FC, Liu CH, Huang TM, Lai CF, Lin YF, Wu VC, Chu TS, Wu MS, Lin SL. (2016, Sep). Losartan reduces ensuing chronic kidney disease and mortality after acute kidney injury. Sci Rep 6:34265.
Chang YT, Yang CC, Pan SY, Chou YH, Chang FC, Lai CF, Tsai MH, Hsu HL, Lin CH, Chiang WC, Wu MS, Chu TS, Chen YM, Lin SL (2016, Feb). DNA methyltransferase inhibition restores erythropoietin production in fibrotic murine kidneys. J Clin Invest, 126(2):721-731.
Chen YT, Chang YT, Pan SY, Chou YH, Chang FC, Yeh PY, Liu YH, Chiang WC, Chen YM, Wu KD, Tsai TJ, Duffield JS, Lin SL (2014, Dec). Lineage tracing reveals distinctive fates for mesothelial cells and submesothelial fibroblasts during peritoneal injury in mice. J Am Soc Nephrol, 25: 2847–2858.
Chang FC, Chiang WC, Tsai MH, Chou YH, Pan SY, Chang YT, Yeh PY, Chen YT, Chiang CK, Chen YM, Chu TS, Wu KD, Lin SL (2014, Jun). Angiopoietin 2 Induced Arterial Stiffness in Chronic Kidney Disease. J Am Soc Nephrol, 25: 1198-1209.
Ren S, Johnson B, Kida Y, Ip C, Davidson KC, Lin SL, Kobayashi A, Lang RA, Hadjantonakis AK, Moon RT, Duffield JS (2013, Jan). LRP-6 is co-receptor for multiple fibrogenic signaling pathways in pericytes and myofibroblasts that are inhibited by DKK-1. Proc Natl Acad Sci USA, 110:1440-1445.
Wu CF, Chiang WC, Lai CF, Chang FC, Chen YT, Chou YH, Wu TH, Linn GR, Ling H, Wu KD, Tsai TJ, Chen YM, Duffield JS, Lin SL (2013, Jan). Transforming growth factor β stimulates profibrotic epithelial signaling to activate pericyte-myofibroblast transition in obstructive kidney fibrosis. Am J Pathol, 182: 118-131.
Chen YT, Chang FC, Wu CF, Chou YH, Hsu HL, Chiang WC, Chen YM, Wu KD, Tsai TJ, Duffield JS, Lin SL. (2011, Dec). Platelet-derived growth factor receptor signaling activates pericyte-myofibroblast transition in obstructive and post-ischemic kidney fibrosis. Kidney Int, 80(11):1170-81.
Lin SL, Chang FC, Schrimpf C, Chen YT, Wu CF, Wu VC, Chiang WC, Kuhnert F, Kuo C, Chen YM, Wu KD, Tsai TJ, Duffield JS. (2011, Feb). Targeting endothelium-pericyte crosstalk by inhibiting VEGF receptor signaling attenuates kidney microvascular rarefaction and fibrosis. Am J Pathol, 178(2): 911-923.
Lin SL, Li B, Rao S, Yeo EJ, Hudson TE, Nowlin BT, Pei H, Chen LJ, Zheng JJ, Carroll TJ, Pollard JW, McMahon AP, Lang RA, Duffield JS. (2010, Mar). Macrophage Wnt7b is critical for kidney repair and regeneration. Proc Natl Acad Sci USA, 107(9):4194-9.
Humphreys BD, Lin SL, Kobayashi A, Hudson TE, Nowlin BT, Bonventre JV, Valerius MT, McMahon AP, Duffield JS (2010, Jan). Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol, 176(1):85-97.
Castaño AP, Lin SL, Surowy T, Nowlin BT, Turlapati SA, Patel T, Singh A, Li S, Lupher Jr. ML, Duffield JS (2009, Nov). Serum amyloid P inhibits fibrosis through FcγR-dependent monocyte-macrophage regulation in vivo. Science Transl Med, 1, 5ra13.
Lin SL, Castaño AP, Nowlin BT, Lupher ML Jr, Duffield JS (2009, Nov). Bone marrow Ly6Chigh monocytes are selectively recruited to injured kidney and differentiate into functionally distinct populations. J Immunol , 183(10):6733-43.
Lin SL, Kisseleva T, Brenner DA, Duffield JS (2008, Dec). Pericytes and perivascular fibroblasts are the primary source of collagen producing cells in obstructive fibrosis of the kidney. Am J Pathol, 173(6):1617-1627.
Lin SL, Chen YM, Chiang WC, Wu KD, Tsai TJ (2008, Sep). Effect of pentoxifylline in addition to losartan on proteinuria and GFR in CKD: A 12-month randomized trial. Am J Kidney Dis,52(3):464-474.
Chen YM, Lin SL, Chiang WC, Wu KD and Tsai TJ (2006, Aug). Pentoxifylline ameliorates proteinuria via suppression of renal MCP-1 in subnephrotic primary glomerular diseases. Kidney Int, 69(8):1410-1415.
Lin SL, Chen RH, Chen YM, Chiang WC, Lai CF, Wu KD, Tsai TJ (2005, Sep). Pentoxifylline attenuates tubulointerstitial fibrosis by blocking Smad3/4-activated transcription and profibrogenic effects of connective tissue growth factor. J Am Soc Nephrol, 16,2702-2713.
Lin SL, Chen YM, Chien CT, Chiang WC, Tsai CC, Tsai TJ (2002, Dec). Pentoxifylline attenuated the renal disease progression in rats with remnant kidney. J Am Soc Nephrol, 13:2916-2929.