Angiotensin II type 1 receptor blockade attenuates renal fibrogenesis in an immune-mediated nephritic kidney through counter-activation of angiotensin II type 2 receptor

The relative roles of angiotensin II (Ang II) type 1 receptor (AT(1)R) and Ang II type 2 receptor (AT(2)R) in immune-mediated nephritis are unknown, and the effect of the blockade of AT(1)R and its indirect counter-activation of AT(2)R relative to the anti-fibrotic action in this disease is unclear. To address this question, we studied the role of AT(1)R and AT(2)R in anti-glomerular basement membrane nephritis in SJL mice. Groups of mice were treated with either an AT(1)R antagonist (CGP-48933; CGP group), an AT(2)R antagonist (PD-123319; PD group), both (CGP/PD group), or a vehicle (PCt group) from Day 29 to 56. At Day 56 post-treatment, fibrosis-related parameters such as interstitial matrix deposition, and the expression of genes of TGF-beta1, plasminogen activator inhibitor-1, and type I collagen were significantly reduced in the kidney in the CGP group. There were no significant effects on these parameters in the PD group. However, this anti-fibrotic action by CGP-48933 was totally abolished by co-treatment with PD-123319 in the CGP/PD group. The gene expression of renin was significantly increased in the kidneys in the CGP and CGP/PD groups, suggesting that CGP-48933 had increased Ang II generation in those groups. In conclusion, counter-activation of AT(2)R by increased Ang II under AT(1)R blockade likely conferred an anti-fibrotic protection in this model.     

Doxycycline accelerates renal cyst growth and fibrosis in the pcy/pcy mouse model of type 3 nephronophthisis, a form of recessive polycystic kidney disease

Nephronophthisis belongs to a family of recessive cystic kidney diseases and may arise from mutations in multiple genes. In this report we have used a spontaneous mouse mutant of type 3 nephronophthisis to examine whether the doxycycline-inducible synthesis of Timp-2, a natural inhibitor of matrix metalloproteinases, can influence renal cyst growth in transgenic mice. Metalloproteinases may exert either a negative or a positive effect on the progression of cystic kidney disease, and we reasoned that this may be most effectively examined by using a natural inhibitor. Surprisingly, already the application of doxycycline, which also inhibits matrix metalloproteinases, accelerated renal cyst growth and led to increased renal fibrosis, an additional effect of Timp-2 was not detected. The positive effect of doxycycline on kidney size was not due to a non-specific “anabolic effect” but was specific for cystic kidneys because it was not observed in non-cystic kidneys. When looking for potential metabolic changes we noticed that the urine of control animals led to an increase in the calcium response of LLC-PK₁ cells, whereas the urine of doxycycline-treated mice showed the opposite effect and even antagonized the urine of control animals. Further experiments demonstrated that the urine of control animals contained a heat-labile, proteinase K-resistant substance which appears to be responsible for the induction of a calcium response in LLC-PK₁ cells. We conclude that doxycycline accelerates cyst growth possibly by the induction of a substance which lowers the intracellular calcium concentration. Our data also add a note of caution when interpreting phenotypes of animal models based upon the tet system. Larissa Osten and Marion Kubitza have contributed equally.     

老年2型糖尿病合并慢性肾脏病患者肠道菌群变化

目的 探讨合并慢性肾脏病的老年2型糖尿病患者肠道菌群变化情况,为后续研究提供参考。 方法 选择2018年11月至2019年7月在我院内科确诊的老年2型糖尿病及并发慢性肾脏病患者作为糖尿病组(20例)及糖尿病肾病组(20例),选择本院健康老年体检者(30例)为对照组。测定各组对象血清甲状旁腺激素(PTH)、超敏C反应蛋白(hs CRP)、血肌酐(Scr)、血磷(P)、血钙(Ca2+)、碱性磷酸酶(ALP)、糖化血红蛋白(HbA1c)水平,同时分析各组对象肠道大肠埃希菌、双歧杆菌、乳杆菌、酵母菌、真杆菌的差异。 结果 糖尿病肾病组患者肠道大肠埃希菌数量高于糖尿病组和对照组,糖尿病组患者肠道大肠埃希菌数量高于对照组(均P2+水平高于糖尿病组和对照组,糖尿病组患者血清Scr、P、Ca2+水平高于对照组(均P2+、HbA1c、ALP、hs CRP水平呈正相关,双歧杆菌、真杆菌数量与Scr、P、Ca2+、HbA1c、ALP、hs CRP水平呈负相关(均P结论 糖尿病肾病患者肠道菌群失调,其特征为大肠埃希菌数量增多,双歧杆菌、真杆菌数量减少。大肠埃希菌数量升高,双歧杆菌和真杆菌数量降低均为糖尿病并发慢性肾脏病的危险因素。     

2型糖尿病与糖尿病肾病患者微炎症及肠道微生物多样性分析

目的 分析2型糖尿病(T2DM)及糖尿病肾病(DKD)患者微炎症情况和肠道微生物多样性。 方法 将2016年4月至2019年7月在我院进行治疗的68例T2DM患者(T2DM组)和57例DKD患者(DKD组)纳入研究,选择同期于我院进行健康体检的36例志愿者作为对照组。收集3组对象一般资料、血液标本和粪便标本,测定血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDLC)、高密度脂蛋白胆固醇(HDLC)、糖化血红蛋白(HbAlc)、空腹血糖(FBG)、超敏C反应蛋白(hsCRP)、白细胞介素6(IL6)水平,并对肠道细菌进行16S rDNA序列测序。比较3组对象一般资料,血液指标,肠道菌群门水平构成情况,肠道菌群多样性,肠道菌属差异性,并对患者炎性指标与菌群种类进行相关性分析。 结果 DKD组患者糖尿病病程长于T2DM组(P结论 2型糖尿病患者普遍存在微炎症和肠道菌群失衡,微炎症程度与肾脏病变和肠道菌群数量密切相关。T2DM与DKD患者在肠道菌群结构上具有一致性和差异性,肠道菌群检测有可能成为预测T2DM患者发生肾脏病变的风险指标。