Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway; Section of Nephrology, University Hospital of North Norway, Tromsø, Norway.
Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA; Medical Clinic and Policlinic IV, Nephrology Center, Department of Internal Medicine, University of Munich, Munich, Germany.
Kidney Int. 2022 Dec;102(6):1345-1358. doi: 10.1016/j.kint.2022.07.033. Epub 2022 Aug 31.
Hyperfiltration is a state of high glomerular filtration rate (GFR) observed in early diabetes that damages glomeruli, resulting in an iterative process of increasing filtration load on fewer and fewer remaining functional glomeruli. To delineate underlying cellular mechanisms of damage associated with hyperfiltration, transcriptional profiles of kidney biopsies from Pima Indians with type 2 diabetes with or without early-stage diabetic kidney disease were grouped into two hyperfiltration categories based on annual iothalamate GFR measurements. Twenty-six participants with a peak GFR measurement within two years of biopsy were categorized as the hyperfiltration group, and 26 in whom biopsy preceded peak GFR by over two years were considered pre-hyperfiltration. The hyperfiltration group had higher hemoglobin A1c, higher urine albumin-to-creatinine ratio, increased glomerular basement membrane width and lower podocyte density compared to the pre-hyperfiltration group. A glomerular 1240-gene transcriptional signature identified in the hyperfiltration group was enriched for endothelial stress response signaling genes, including endothelin-1, tec-kinase and transforming growth factor-β1 pathways, with the majority of the transcripts mapped to endothelial and inflammatory cell clusters in kidney single cell transcriptional data. Thus, our analysis reveals molecular pathomechanisms associated with hyperfiltration in early diabetic kidney disease involving putative ligand-receptor pairs with downstream intracellular targets linked to cellular crosstalk between endothelial and mesangial cells.
高滤过是在糖尿病早期观察到的肾小球滤过率（GFR）升高的状态，它会损害肾小球，导致滤过负荷在越来越少的剩余功能肾小球上不断增加。为了阐明与高滤过相关的损伤的潜在细胞机制，根据每年碘酞酸盐 GFR 测量值，将患有 2 型糖尿病和早期糖尿病肾病的皮马印第安人肾活检组织的转录谱分为两类高滤过类别。26 名参与者在活检后两年内进行了最高 GFR 测量，被归类为高滤过组，而 26 名活检前最高 GFR 超过两年的参与者被认为是高滤过前组。与高滤过前组相比，高滤过组的血红蛋白 A1c 更高，尿白蛋白与肌酐比值更高，肾小球基底膜宽度增加，足细胞密度降低。在高滤过组中鉴定出的肾小球 1240 个基因转录特征，富含内皮应激反应信号基因，包括内皮素-1、tec-激酶和转化生长因子-β1 途径，大多数转录物映射到肾脏单细胞转录数据中的内皮和炎性细胞簇。因此，我们的分析揭示了与早期糖尿病肾病中高滤过相关的分子发病机制，涉及潜在的配体-受体对及其下游细胞内靶标，这些靶标与内皮细胞和系膜细胞之间的细胞串扰有关。
