Truncated suPAR simultaneously causes kidney disease and autoimmune diabetes mellitus

Soluble urokinase-type plasminogen activator receptor (suPAR) is a risk factor for kidney diseases. Here we report the presence of C-terminal suPAR fragment, D2D3, in patients with diabetic nephropathy. D2D3-positive human sera inhibited glucose-stimulated insulin release in human islets and were associated with patients requiring insulin therapy. D2D3 transgenic mice presented kidney disease and diabetes marked by decreased levels of insulin and C-peptide, impaired glucose-stimulated insulin secretion, decreased pancreatic β-cell mass, and high fasting glucose. D2D3 fragment dysregulated glucose-induced cytoskeletal dynamics, impaired maturation and trafficking of insulin granules, and inhibited bioenergetics of β-cells in culture. An anti-uPAR antibody restored β-cell function in D2D3 transgenic mice. We show that the D2D3 fragment injures the kidney and pancreas, offering a unique dual therapeutic approach for kidney diseases and insulin-dependent diabetes. Summary Proteolytic suPAR fragment, D2D3, simultaneously injures two organs, the kidney and pancreas, thus causing a dual organ disease.

[1]  J. Markmann,et al.  The IGFBP3/TMEM219 pathway regulates beta cell homeostasis , 2022, Nature Communications.

[2]  S. Loosen,et al.  Inflammation, Hyperglycemia, and Adverse Outcomes in Individuals With Diabetes Mellitus Hospitalized for COVID-19 , 2022 .

[3]  R. Stevens,et al.  Visualizing insulin vesicle neighborhoods in β cells by cryo–electron tomography , 2020, Science Advances.

[4]  S. Loosen,et al.  Soluble Urokinase Receptor (SuPAR) in COVID-19-Related AKI. , 2020, Journal of the American Society of Nephrology : JASN.

[5]  N. Rovina,et al.  Soluble urokinase plasminogen activator receptor (suPAR) as an early predictor of severe respiratory failure in patients with COVID-19 pneumonia , 2020, Critical Care.

[6]  D. Wedekind,et al.  Pancreas Pathology of Latent Autoimmune Diabetes in Adults (LADA) in Patients and in a LADA Rat Model Compared With Type 1 Diabetes , 2020, Diabetes.

[7]  Jian Cai,et al.  uPAR isoform 2 forms a dimer and induces severe kidney disease in mice. , 2019, The Journal of clinical investigation.

[8]  J. Floege,et al.  High-fat diet-induced obesity causes an inflammatory microenvironment in the kidneys of aging Long-Evans rats , 2019, Journal of Inflammation.

[9]  Sushrut S. Waikar,et al.  The single-cell transcriptomic landscape of early human diabetic nephropathy , 2019, Proceedings of the National Academy of Sciences.

[10]  M. Bugliani,et al.  Insulin secretory granules labelled with phogrin-fluorescent proteins show alterations in size, mobility and responsiveness to glucose stimulation in living β-cells , 2019, Scientific Reports.

[11]  M. Sulaiman,et al.  Diabetic nephropathy: recent advances in pathophysiology and challenges in dietary management , 2019, Diabetology & Metabolic Syndrome.

[12]  P. Pozzilli,et al.  Latent Autoimmune Diabetes in Adults: Current Status and New Horizons , 2018, Endocrinology and metabolism.

[13]  K. Jalink,et al.  Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells , 2017, eLife.

[14]  Haoran Dai,et al.  Research Progress on Mechanism of Podocyte Depletion in Diabetic Nephropathy , 2017, Journal of diabetes research.

[15]  N. Heyne,et al.  Soluble urokinase receptor (suPAR) predicts microalbuminuria in patients at risk for type 2 diabetes mellitus , 2017, Scientific Reports.

[16]  D. Scadden,et al.  Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease , 2016, Nature Medicine.

[17]  M. Rastaldi,et al.  Full-length soluble urokinase plasminogen activator receptor down-modulates nephrin expression in podocytes , 2015, Scientific Reports.

[18]  Z. Dong,et al.  Multiple myeloma with a previous diagnosis of focal segmental glomerulosclerosis: A case report and review of the literature , 2015, Oncology letters.

[19]  T. Hansen,et al.  Increased plasma concentrations of midregional proatrial natriuretic Peptide is associated with risk of cardiorenal dysfunction in type 1 diabetes. , 2015, American journal of hypertension.

[20]  G. Rutter,et al.  Pancreatic β-cell identity, glucose sensing and the control of insulin secretion. , 2015, The Biochemical journal.

[21]  R. Leslie,et al.  Latent autoimmune diabetes of the adult: current knowledge and uncertainty , 2015, Diabetic medicine : a journal of the British Diabetic Association.

[22]  L. Levitsky,et al.  Role of growth factors in control of pancreatic beta cell mass: focus on betatrophin. , 2014, Current opinion in pediatrics.

[23]  J. Eugen-Olsen,et al.  The molecular crystal ball , 2014 .

[24]  A. Araszkiewicz,et al.  Association Between IL-6 Concentration and Diabetes-Related Variables in DM1 Patients with and without Microvascular Complications , 2013, Inflammation.

[25]  J. Jeppesen,et al.  The immune marker soluble urokinase plasminogen activator receptor is associated with new‐onset diabetes in non‐smoking women and men , 2012, Diabetic medicine : a journal of the British Diabetic Association.

[26]  Josef Coresh,et al.  Chronic kidney disease , 2012, The Lancet.

[27]  J. Hall,et al.  Disruption of Thyroid Hormone Activation in Type 2 Deiodinase Knockout Mice Causes Obesity With Glucose Intolerance and Liver Steatosis Only at Thermoneutrality , 2011, Diabetes.

[28]  T. Hansen,et al.  Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population , 2010, Journal of internal medicine.

[29]  Zhanxiang Wang,et al.  Mechanisms of biphasic insulin-granule exocytosis – roles of the cytoskeleton, small GTPases and SNARE proteins , 2009, Journal of Cell Science.

[30]  K. Hongo,et al.  A case report and review of the literature , 2006, Journal of Neuro-Oncology.

[31]  J. Miyazaki,et al.  Pancreatic beta cell line MIN6 exhibits characteristics of glucose metabolism and glucose-stimulated insulin secretion similar to those of normal islets , 1993, Diabetologia.

[32]  H. Chapman,et al.  Urokinase receptor and integrin interactions. , 2003, Current pharmaceutical design.

[33]  M. A. Kelly,et al.  Molecular aspects of type 1 diabetes , 2003, Molecular pathology : MP.

[34]  F. Blasi,et al.  Metalloproteases Cleave the Urokinase-Type Plasminogen Activator Receptor in the D1-D2 Linker Region and Expose Epitopes not Present in the intact Soluble Receptor , 2002, Thrombosis and Haemostasis.

[35]  S. Mustjoki,et al.  Enhanced release of soluble urokinase receptor by endothelial cells in contact with peripheral blood cells , 2000, FEBS letters.

[36]  S. Mustjoki,et al.  Soluble urokinase receptor levels correlate with number of circulating tumor cells in acute myeloid leukemia and decrease rapidly during chemotherapy. , 2000, Cancer research.

[37]  F. Blasi,et al.  Shedding and cleavage of the urokinase receptor (uPAR): identification and characterisation of uPAR fragments in vitro and in vivo , 2000, FEBS letters.

[38]  L. Liotta,et al.  Integrin alphavbeta3 mediates chemotactic and haptotactic motility in human melanoma cells through different signaling pathways. , 1996, The Journal of biological chemistry.

[39]  J. Coresh,et al.  A tripartite complex of suPAR, APOL1 risk variants and alpha(v)beta(3) integrin on podocytes mediates chronic kidney disease , 2022 .