代谢综合征环境下肾结石形成机制的初步实验研究
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摘要
第一部分肾小管上皮细胞在与脂肪细胞、巨噬细胞共培养条件下促进结晶形成及旁分泌作用的研究
研究背景
肾结石是一种严重影响人体健康的临床常见病和多发病，虽然肾结石的诊断及治疗技术在过去的几十年中取得了巨大的进步，但其发病率和复发率仍高居不下，究其原因主要是由于目前对肾结石的发病机制还不明确，相关研究进展也较为缓慢。便捷、稳定的实验细胞和动物草酸钙结石模型是研究肾结石临床和基础研究的重要手段和工具，对探索肾结石产生和防治机制具有重要意义。
近年来大宗的流行病学研究发现，肥胖、胰岛素抵抗、2型糖尿病、尿pH值降低、高血压等代谢因素不单是肾结石发生的危险因素，而且还与结石的演进密切相关。目前代谢综合征中各个因素具体如何参与结石形成过程的研究相对薄弱。其对结石生成的影响尚未见相关基础研究报道。
从肾结石成分来看，人类肾结石主要以含钙结石为主，其中又以草酸钙结石最多，约占结石总数的80%左右。主流观点认为尿液中草酸钙晶体的成核、生长、聚集是草酸钙结石形成的主要机制。尿液中结石成分过饱和析出只是结石生成条件之一，在正常生理状态下，肾小管中的草酸钙晶体由于尿液的冲刷作用而随尿液排出，无法在肾小管中聚集形成结石，只有在肾小管上皮损伤情况下，尿中的草酸钙晶体才能够黏附、生长和聚集于。肾内或肾乳头表面形成结石斑，并经过一系列反应最终生成草酸钙结石。因而，草酸钙结晶的沉积被认为是草酸钙结石生成的重要基础，建立一种成熟、稳定的草酸钙结晶模型对研究草酸钙结石早期生成机制具有重要作用。
研究目的
通过本研究探索和建立涉及肾小管上皮细胞、巨噬细胞和脂肪细胞的体外实验体系，以模拟代谢综合征下细胞环境，并借助这一细胞模型研究三种细胞间的相互作用以及与晶体之间的作用。
研究方法
将小鼠肾小管上皮细胞(M-1)与小鼠脂肪细胞(3T3-L1)和/或巨噬细胞(RAW264.7)进行共培养48小时，然后将一水草酸钙(COM)晶体作用于肾小管上皮细胞（M-1）。然后测定促炎因子骨桥蛋白(OPN)、单核细胞趋化因子1(MCP-1)、肿瘤坏死因子-α(TNF-α)、白介素6（IL-6）以及抗炎因子脂联素（APN）的表达水平，并且测定肾小管上皮细胞上晶体附着的含量。
研究结果
炎症因子骨桥蛋白(OPN)、单核细胞趋化因子1(MCP-1)、肿瘤坏死因子α(TNF-α)在共培养组中有显著的上调。骨桥蛋白(OPN)的过表达只发生在含有巨噬细胞(RAW264.7)的共培养组中，而肿瘤坏死因子-α（TNF-α）和单核细胞趋化因子1(MCP-1)在含有脂肪细胞(3T3-L1)的共培养组中出现。而脂联素（APN）的表达在三种细胞共培养的条件下是下调的。这些炎症因子的改变发生于空间隔离互不接触的共培养体系中，从而提示肾小管上皮细胞（M-1）与脂肪细胞(3T3-L1)和巨噬细胞(RAW264.7)之间存在着功能性互动，而且这种相互作用很可能是通过培养液内的可溶性蛋白质介导的。而将肾小管上皮细胞（M-1）与脂肪细胞(3T3-L1)和巨噬细胞(RAW264.7).共同培养后还同时促进了一水草酸钙晶体（COM）对肾小管上皮细胞（M-1）的吸附。
研究结论
1.通过将肾小管上皮细胞（M-1）与脂肪细胞(3T3-L1)和巨噬细胞(RAW264.7)共培养模拟的代谢综合征环境下，首次发现多种促炎因子的上调和抗炎因子的下调。
2.将肾小管上皮细胞（M-1）与脂肪细胞(3T3-L1)和巨噬细胞(RAW264.7)共培养可以促进肾小管上皮细胞对一水草酸钙晶体（COM）的吸附作用，而这一作用至少部分是通过旁分泌机制实现的。这很可能是代谢综合征环境下肾结石形成的重要机制之一。
第二部分代谢综合征小鼠肾草酸钙结晶模型中炎症因子的改变及脂联素（APN）对结晶形成抑制作用的研究
研究目的
通过本研究探索和建立代谢综合征环境下肾结晶小鼠模型，并利用这一模型研究肾结石形成可能的机制，同时观察和评价脂联素（APN）对肾结晶形成的预防作用。
研究方法
本研究利用乙醛酸盐按50mg/kg/天×6天诱导8周龄雄性野生型和ob/ob型小鼠产生肾结晶沉积。小鼠分为三组：野生型(+/+)组(对照组, n=12)；代谢综合征ob/ob型小鼠组(ob/ob组, n=12)；ob/ob型小鼠+APN注射组(APN组，n=12)；收集血和尿样进行生化分析，另外收集肾脏标本评估结石的形成和相关炎症细胞因子(OPN)，(MCP-1)和(APN)的表达。还进行了TUNEL染色以评估细胞凋亡水平。
研究结果
对照组小鼠组(+/+组)没有发现结石形成，而在代谢综合征小鼠模型（ob/ob组）发现了显著的肾结晶的沉积，但是这些肾结晶在APN干预后（APN组）明显减少。在代谢综合征小鼠模型（ob/ob组）发现促炎细胞因子OPN和MCP-1有明显的上调而抗炎细胞因子APN有明显的下调。TUNEL染色显示ob/ob组和APN干预组均有凋亡细胞的增加而前者更加明显。
研究结论
本研究成功建立了代谢综合征环境下小鼠肾结晶模型，并借此提供了明确的证据显示代谢综合征环境下可以促进肾结石的形成，而这一过程可能涉及肾组织的炎症反应和凋亡。另外，这也是首次发现脂联素对肾结石的预防保护作用，此作用与对炎症和凋亡的抑制有关。
Part1：AParacrine Loop involving renal tubular cells,Adipocytes andMacropages Aggravates Inflammatory Changes to promote kidney stoneformation in metabolic syndrome
Background：
Urolithiasis is a common urological disorder with a lifetime risk of10–12%among thepopulations of industrialized countries. In particular, the prevalence of kidney stones hasincreased, worldwide, over the past few decades. Dietary and lifestyle factors play anincreasing role in the risk of stone disease, with diets high in protein and fat raising the riskof stone formation. Recent studies have indicated that nephrolithiasis is linked to otherchronic diseases, such as diabetes mellitus, obesity and metabolic syndrome (MetS).
MetS involves a constellation of manifestations, including visceral fat obesity, impairedglucose metabolism, atherogenic dyslipidemia, and hypertension. There is compellingevidence that obesity is a crucial etiologic factor in the development of MetS, with obesityalso being considered a metabolic disease and a chronic, low-grade, inflammatory disease.Recent studies have revealed that adipose tissue in MetS is characterized by the infiltrationof macrophages, which are responsible for the production of inflammatory cytokines.
Despite a large amount of epidemiologic evidence supporting the association betweenMetS and kidney stone formation, the mechanism linking MetS with the formation ofkidney stones is largely unknown. Our previous research in mice showed that MetSaggravates the formation of calcium oxalate kidney stones by enhancing inflammation. Tofurther elucidate how MetS promotes susceptibility to urolithiasis before and during kidneystone formation, we simulated MetS by coculturing renal tubular epithelial cells with adipocytes and/or macrophages. We hypothesized that adipocytes and macrophagesincreased their cellular interactions to accelerate stone formation.
Objective:
The aim of this study is to establish an in vitro experimental system composed of renaltubular cells with adipocytes and macrophages to simulate metabolic syndrome, and thenexamine the molecular mechanism whereby these cells communicate.
Methods:
Mouse renal tubular cells (M-1s) is cocultured with adipocytes (3T3-L1s) or/andmacrophages (RAW264s). The calcium oxalate monohydrate (COM) crystals wereexposed onto M-1cells after48hours of coculture and quantification of adherent COMcrystals were evaluated. Expression analysis of kidney stone-and adipocytes-relatedinflammatory genes and proteins were performed.
Results:
Inflammatory including monocyte chemoattractant protein-1(MCP-1),osteopontin (OPN)and tumor necrosis factor-α (TNF-α) were up-regulated markedly in coculture groups.OPNover-expression of M-1occurs in coculture systems contained RAW264. TNF-α andMCP-1over-expression are detected from coculture systems contained3T3-L1. Suchinflammatory changes are induced by the coculture without direct contact, suggesting therole of soluble factors. Coculturing M-1s with3T3-L1s and RAW264s resulted insignificantly increased adhesion of calcium oxalate monohydrate (COM) crystals to M-1.Conclusion: Our results postulate that paracrine loop involving renal tubular cells,adipocytes and/or macrophages aggravates inflammatory changes of renal tubular cells inmetabolic syndrome or obesity, which may promote the susceptibility of urolithiasis.
Part2：Inflammatory Changes and Effect ofAdiponectin on KidneyCrystal Formation in Metabolic Syndrome Model Mice
Objective:
Although an epidemiological link between the metabolic syndrome and kidney stoneformation has been reported, the mechanism by which metabolic syndrome promoteskidney stone formation has yet to be elucidated. We investigated calcium oxalate (CaOx)kidney stone formation in a mouse metabolic syndrome model.The aims of the presentstudy were to elucidate a possible mechanism of kidney crystal formation by using ametabolic syndrome (MetS) mouse model and to assess the effectiveness of adiponectintreatment for the prevention of kidney crystals.
Methord:
We induced CaOx crystal deposition in8-week-old male ob/ob mouse, and a control strain,Wild-type(+/+) mouse, by administering50mg/kg glyoxylate (GOx) for6days. Mice weredivided into3groups: Wild-type (+/+) mouse(control, n=12); ob/ob mouse (stone forming,n=12); APN treatment (n=12);Urine and blood samples were collected for biochemistrytesting, and the kidneys were harvested for estimation of crystal deposition anddeterminations of the expression of osteopontin(OPN),monocyte chemoattractantprotein-1(MCP-1) andAdiponectin(APN).
Results:
Wild-type (+/+) mice showed no kidney crystal formation, whereas ob/ob mice showedcrystal depositions in their renal tubules. However, this deposition was remarkably reducedby adiponectin.Significant upregulation of both inflammatory OPN and MCP-1was seenin the kidneys of ob/ob mice and whereas downregulation of antiinflammatory cytokineAPN. By TUNEL staining, ob/ob and ob/ob+APN kidneys showed stained nuclei in thearea from the cortex to medulla, with the cortico-medullary junction showing particularlystrong staining.
Conclusion:
The results of this study provide compelling evidence that the mechanism of kidney crystalformation in the MetS environment involves the progression of an inflammation, mightincluding oxidative stress and apoptosis in renal tissues. This is the first report to prove thepreventive effect of adiponectin treatment for kidney crystal formation by renoprotectiveactivities and inhibition of inflammation and apoptosis.
研究背景
肾结石是一种严重影响人体健康的临床常见病和多发病，虽然肾结石的诊断及治疗技术在过去的几十年中取得了巨大的进步，但其发病率和复发率仍高居不下，究其原因主要是由于目前对肾结石的发病机制还不明确，相关研究进展也较为缓慢。便捷、稳定的实验细胞和动物草酸钙结石模型是研究肾结石临床和基础研究的重要手段和工具，对探索肾结石产生和防治机制具有重要意义。
近年来大宗的流行病学研究发现，肥胖、胰岛素抵抗、2型糖尿病、尿pH值降低、高血压等代谢因素不单是肾结石发生的危险因素，而且还与结石的演进密切相关。目前代谢综合征中各个因素具体如何参与结石形成过程的研究相对薄弱。其对结石生成的影响尚未见相关基础研究报道。
从肾结石成分来看，人类肾结石主要以含钙结石为主，其中又以草酸钙结石最多，约占结石总数的80%左右。主流观点认为尿液中草酸钙晶体的成核、生长、聚集是草酸钙结石形成的主要机制。尿液中结石成分过饱和析出只是结石生成条件之一，在正常生理状态下，肾小管中的草酸钙晶体由于尿液的冲刷作用而随尿液排出，无法在肾小管中聚集形成结石，只有在肾小管上皮损伤情况下，尿中的草酸钙晶体才能够黏附、生长和聚集于。肾内或肾乳头表面形成结石斑，并经过一系列反应最终生成草酸钙结石。因而，草酸钙结晶的沉积被认为是草酸钙结石生成的重要基础，建立一种成熟、稳定的草酸钙结晶模型对研究草酸钙结石早期生成机制具有重要作用。
研究目的
通过本研究探索和建立涉及肾小管上皮细胞、巨噬细胞和脂肪细胞的体外实验体系，以模拟代谢综合征下细胞环境，并借助这一细胞模型研究三种细胞间的相互作用以及与晶体之间的作用。
研究方法
将小鼠肾小管上皮细胞(M-1)与小鼠脂肪细胞(3T3-L1)和/或巨噬细胞(RAW264.7)进行共培养48小时，然后将一水草酸钙(COM)晶体作用于肾小管上皮细胞（M-1）。然后测定促炎因子骨桥蛋白(OPN)、单核细胞趋化因子1(MCP-1)、肿瘤坏死因子-α(TNF-α)、白介素6（IL-6）以及抗炎因子脂联素（APN）的表达水平，并且测定肾小管上皮细胞上晶体附着的含量。
研究结果
炎症因子骨桥蛋白(OPN)、单核细胞趋化因子1(MCP-1)、肿瘤坏死因子α(TNF-α)在共培养组中有显著的上调。骨桥蛋白(OPN)的过表达只发生在含有巨噬细胞(RAW264.7)的共培养组中，而肿瘤坏死因子-α（TNF-α）和单核细胞趋化因子1(MCP-1)在含有脂肪细胞(3T3-L1)的共培养组中出现。而脂联素（APN）的表达在三种细胞共培养的条件下是下调的。这些炎症因子的改变发生于空间隔离互不接触的共培养体系中，从而提示肾小管上皮细胞（M-1）与脂肪细胞(3T3-L1)和巨噬细胞(RAW264.7)之间存在着功能性互动，而且这种相互作用很可能是通过培养液内的可溶性蛋白质介导的。而将肾小管上皮细胞（M-1）与脂肪细胞(3T3-L1)和巨噬细胞(RAW264.7).共同培养后还同时促进了一水草酸钙晶体（COM）对肾小管上皮细胞（M-1）的吸附。
研究结论
1.通过将肾小管上皮细胞（M-1）与脂肪细胞(3T3-L1)和巨噬细胞(RAW264.7)共培养模拟的代谢综合征环境下，首次发现多种促炎因子的上调和抗炎因子的下调。
2.将肾小管上皮细胞（M-1）与脂肪细胞(3T3-L1)和巨噬细胞(RAW264.7)共培养可以促进肾小管上皮细胞对一水草酸钙晶体（COM）的吸附作用，而这一作用至少部分是通过旁分泌机制实现的。这很可能是代谢综合征环境下肾结石形成的重要机制之一。
第二部分代谢综合征小鼠肾草酸钙结晶模型中炎症因子的改变及脂联素（APN）对结晶形成抑制作用的研究
研究目的
通过本研究探索和建立代谢综合征环境下肾结晶小鼠模型，并利用这一模型研究肾结石形成可能的机制，同时观察和评价脂联素（APN）对肾结晶形成的预防作用。
研究方法
本研究利用乙醛酸盐按50mg/kg/天×6天诱导8周龄雄性野生型和ob/ob型小鼠产生肾结晶沉积。小鼠分为三组：野生型(+/+)组(对照组, n=12)；代谢综合征ob/ob型小鼠组(ob/ob组, n=12)；ob/ob型小鼠+APN注射组(APN组，n=12)；收集血和尿样进行生化分析，另外收集肾脏标本评估结石的形成和相关炎症细胞因子(OPN)，(MCP-1)和(APN)的表达。还进行了TUNEL染色以评估细胞凋亡水平。
研究结果
对照组小鼠组(+/+组)没有发现结石形成，而在代谢综合征小鼠模型（ob/ob组）发现了显著的肾结晶的沉积，但是这些肾结晶在APN干预后（APN组）明显减少。在代谢综合征小鼠模型（ob/ob组）发现促炎细胞因子OPN和MCP-1有明显的上调而抗炎细胞因子APN有明显的下调。TUNEL染色显示ob/ob组和APN干预组均有凋亡细胞的增加而前者更加明显。
研究结论
本研究成功建立了代谢综合征环境下小鼠肾结晶模型，并借此提供了明确的证据显示代谢综合征环境下可以促进肾结石的形成，而这一过程可能涉及肾组织的炎症反应和凋亡。另外，这也是首次发现脂联素对肾结石的预防保护作用，此作用与对炎症和凋亡的抑制有关。
Part1：AParacrine Loop involving renal tubular cells,Adipocytes andMacropages Aggravates Inflammatory Changes to promote kidney stoneformation in metabolic syndrome
Background：
Urolithiasis is a common urological disorder with a lifetime risk of10–12%among thepopulations of industrialized countries. In particular, the prevalence of kidney stones hasincreased, worldwide, over the past few decades. Dietary and lifestyle factors play anincreasing role in the risk of stone disease, with diets high in protein and fat raising the riskof stone formation. Recent studies have indicated that nephrolithiasis is linked to otherchronic diseases, such as diabetes mellitus, obesity and metabolic syndrome (MetS).
MetS involves a constellation of manifestations, including visceral fat obesity, impairedglucose metabolism, atherogenic dyslipidemia, and hypertension. There is compellingevidence that obesity is a crucial etiologic factor in the development of MetS, with obesityalso being considered a metabolic disease and a chronic, low-grade, inflammatory disease.Recent studies have revealed that adipose tissue in MetS is characterized by the infiltrationof macrophages, which are responsible for the production of inflammatory cytokines.
Despite a large amount of epidemiologic evidence supporting the association betweenMetS and kidney stone formation, the mechanism linking MetS with the formation ofkidney stones is largely unknown. Our previous research in mice showed that MetSaggravates the formation of calcium oxalate kidney stones by enhancing inflammation. Tofurther elucidate how MetS promotes susceptibility to urolithiasis before and during kidneystone formation, we simulated MetS by coculturing renal tubular epithelial cells with adipocytes and/or macrophages. We hypothesized that adipocytes and macrophagesincreased their cellular interactions to accelerate stone formation.
Objective:
The aim of this study is to establish an in vitro experimental system composed of renaltubular cells with adipocytes and macrophages to simulate metabolic syndrome, and thenexamine the molecular mechanism whereby these cells communicate.
Methods:
Mouse renal tubular cells (M-1s) is cocultured with adipocytes (3T3-L1s) or/andmacrophages (RAW264s). The calcium oxalate monohydrate (COM) crystals wereexposed onto M-1cells after48hours of coculture and quantification of adherent COMcrystals were evaluated. Expression analysis of kidney stone-and adipocytes-relatedinflammatory genes and proteins were performed.
Results:
Inflammatory including monocyte chemoattractant protein-1(MCP-1),osteopontin (OPN)and tumor necrosis factor-α (TNF-α) were up-regulated markedly in coculture groups.OPNover-expression of M-1occurs in coculture systems contained RAW264. TNF-α andMCP-1over-expression are detected from coculture systems contained3T3-L1. Suchinflammatory changes are induced by the coculture without direct contact, suggesting therole of soluble factors. Coculturing M-1s with3T3-L1s and RAW264s resulted insignificantly increased adhesion of calcium oxalate monohydrate (COM) crystals to M-1.Conclusion: Our results postulate that paracrine loop involving renal tubular cells,adipocytes and/or macrophages aggravates inflammatory changes of renal tubular cells inmetabolic syndrome or obesity, which may promote the susceptibility of urolithiasis.
Part2：Inflammatory Changes and Effect ofAdiponectin on KidneyCrystal Formation in Metabolic Syndrome Model Mice
Objective:
Although an epidemiological link between the metabolic syndrome and kidney stoneformation has been reported, the mechanism by which metabolic syndrome promoteskidney stone formation has yet to be elucidated. We investigated calcium oxalate (CaOx)kidney stone formation in a mouse metabolic syndrome model.The aims of the presentstudy were to elucidate a possible mechanism of kidney crystal formation by using ametabolic syndrome (MetS) mouse model and to assess the effectiveness of adiponectintreatment for the prevention of kidney crystals.
Methord:
We induced CaOx crystal deposition in8-week-old male ob/ob mouse, and a control strain,Wild-type(+/+) mouse, by administering50mg/kg glyoxylate (GOx) for6days. Mice weredivided into3groups: Wild-type (+/+) mouse(control, n=12); ob/ob mouse (stone forming,n=12); APN treatment (n=12);Urine and blood samples were collected for biochemistrytesting, and the kidneys were harvested for estimation of crystal deposition anddeterminations of the expression of osteopontin(OPN),monocyte chemoattractantprotein-1(MCP-1) andAdiponectin(APN).
Results:
Wild-type (+/+) mice showed no kidney crystal formation, whereas ob/ob mice showedcrystal depositions in their renal tubules. However, this deposition was remarkably reducedby adiponectin.Significant upregulation of both inflammatory OPN and MCP-1was seenin the kidneys of ob/ob mice and whereas downregulation of antiinflammatory cytokineAPN. By TUNEL staining, ob/ob and ob/ob+APN kidneys showed stained nuclei in thearea from the cortex to medulla, with the cortico-medullary junction showing particularlystrong staining.
Conclusion:
The results of this study provide compelling evidence that the mechanism of kidney crystalformation in the MetS environment involves the progression of an inflammation, mightincluding oxidative stress and apoptosis in renal tissues. This is the first report to prove thepreventive effect of adiponectin treatment for kidney crystal formation by renoprotectiveactivities and inhibition of inflammation and apoptosis.
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