Immunity and inflammation in diabetic kidney disease: translating mechanisms to biomarkers and treatment targets

Pichler, Raimund; Afkarian, Maryam; Dieter, Brad P.; Tuttle, Katherine R.

doi:10.1152/ajprenal.00314.2016

Cited by 200 publications

(199 citation statements)

References 207 publications

(185 reference statements)

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“…Immune cell infiltration is a well-known feature of diabetic nephropathy. (59) We observed an increased number of T-cells, B-cells, plasma cells, and mononuclear cells in two of three diabetic samples. The two patients with an increased number of immune cells also had mild to moderate proteinuria and interstitial fibrosis.…”

Section: Discussionmentioning

confidence: 63%

The Single Cell Transcriptomic Landscape of Early Human Diabetic Nephropathy

Wilson

Kirita

et al. 2019

Preprint

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Diabetic nephropathy is characterized by damage to both the glomerulus and tubulointerstitium, but relatively little is known about accompanying cell-specific changes in gene expression. We performed unbiased single nucleus RNA sequencing (snRNAseq) on cryopreserved human diabetic kidney samples to generate 23,980 single nucleus transcriptomes from three control and three early diabetic nephropathy samples. All major cell types of the kidney were represented in the final dataset. Side by side comparison demonstrated cell-typespecific changes in gene expression that are important for ion transport, angiogenesis, and immune cell activation. In particular, we show that the diabetic loop of Henle, late distal convoluted tubule, and principal cells all adopt a gene expression signature consistent with increased potassium secretion, including alterations in Na-K + -ATPase, WNK1, mineralocorticoid receptor and NEDD4L expression, as well as decreased paracellular calcium and magnesium reabsorption. We also identify strong angiogenic signatures in glomerular cell types, proximal convoluted tubule, distal convoluted tubule and principal cells. Taken together, these results suggest that increased potassium secretion and angiogenic signaling represent early kidney responses in human diabetic nephropathy. Significance StatementSingle nucleus RNA sequencing revealed gene expression changes in early diabetic nephropathy that promote urinary potassium secretion and decreased calcium and magnesium reabsorption. Multiple cell types exhibited angiogenic signatures, which may represent early signs of aberrant angiogenesis. These alterations may help to identify biomarkers for disease progression or signaling pathways amenable to early intervention.

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Section: Discussionmentioning

confidence: 63%

The Single Cell Transcriptomic Landscape of Early Human Diabetic Nephropathy

Wilson

Kirita

et al. 2019

Preprint

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“…DN is characterized by functional and structural changes, such as proteinuria, decline in the glomerular filtration rate (GFR), excessive deposition of extracellular matrix (ECM), thickening of the glomerular basement membrane (GBM) and hypertrophy, which ultimately result in glomerulosclerosis and tubulointerstitial fibrosis [2,3]. Many researchers are convinced that microinflammation and fibrosis play central roles in the development of DN and are the common pathways for progression to ESRD [4,5]. The various proinflammatory molecules and pathways implicated in DN include proinflammatory cytokines, chemokines, adhesion molecules, Toll-like receptors (TLRs), transcription factors and nuclear receptors.…”

Section: Introductionmentioning

confidence: 99%

High Mobility Group Box1 Inhibitor Glycyrrhizic Acid Attenuates Kidney Injury in Streptozotocin-Induced Diabetic Rats

Zhang

Chen

et al. 2017

Kidney Blood Press Res

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Background/Aims: High mobility group box 1 (HMGB1) is an important mediator of the inflammatory response. It has been implicated in the pathogenesis of autoimmune diseases, atherosclerosis, and obesity. However, the effects of HMGB1 on diabetic nephropathy remain unclear. Here, we investigated the potential roles and mechanisms of an HMGB1 inhibitor, glycyrrhizic acid (GA), in renal injury with the streptozotocin (STZ)-induced rat model. Methods: The diabetic rat was generated by intraperitoneal injection of STZ and then treated with the HMGB1 inhibitor GA or saline for 8 weeks. Rats were randomly divided into three groups: the normal control and saline group (Control), the diabetic rats with saline group (Diabetic) and the diabetic rats plus GA group (Diabetic+GA). Peripheral blood was obtained for measurements of blood glucose, TNF-a, IL-6 and IL-1β. The mRNA levels of proinflammatory cytokines (TNF-a, IL-6 and IL-1β), chemokines (MCP-1), intercellular adhesion molecules (ICAM-1) and TGF-β1 in the kidneys were evaluated by quantitative real-time PCR. The protein levels of phosphorylated(p) and total(t) p38 MAPK, JNK, ERK, and NF-κB were measured by western blot. Results: We found that diabetic rats showed obvious renal lesions, an elevated urinary albumin/creatinine ratio (UACR) and increased expression levels of TGF-β1 and Col-IV in the kidneys, accompanied by significantly enhanced expression levels of HMGB1, receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR-4) in the kidney tissue. Furthermore, the GA treatment significantly reduced the UAC levels, ameliorated renal injury, and decreased the TNF-α, 1L-6, IL-1β, MCP-1, ICAM-1, TGF-β1 and Col-IV levels. Importantly, the expression levels of HMGBI, RAGE and TLR4 in the kidney tissues of the diabetic rats were also inhibited by the GA treatment. Furthermore, the GA treatment significantly reduced the phosphorylation levels of ERK and p38 MAPK and suppressed NF-κB translocation from the cytoplasm to the nucleus. Conclusion: Our findings indicate that the HMGB1 inhibitor GA may improve renal injury and inflammatory responses in diabetic rats by regulating RAGE/TLR4-related ERK and p38 MAPK/NF-κB activation.

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“…Despite tremendous efforts of the clinical and translational research community and enormous amounts of scientific evidence discovered about various disease mechanisms, no others have successfully translated to a new treatment for DKD. Processes like fibrosis and inflammation undoubtedly contribute in major ways to the pathogenesis of DKD, but many attempts to translate these mechanisms to therapeutic targets have not yet succeeded (3–7). This consequence is likely due to a number of issues in the design and conduct of clinical trials, lack of validated DKD biomarkers, and barriers in the regulatory and business domains (8).…”

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confidence: 99%