ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005


The Latest on Twitter

Kidney Week

Abstract: TH-PO215

Truncated suPAR Simultaneously Causes Kidney Disease and Diabetes Mellitus

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic


  • Zhu, Ke, Rush University Medical Center, Chicago, Illinois, United States
  • Mukherjee, Kamalika, Harvard Medical School, Boston, Massachusetts, United States
  • Wei, David Changli, Rush University Medical Center, Chicago, Illinois, United States
  • Hayek, Salim, University of Michigan, Ann Arbor, Michigan, United States
  • Collins, Agnieszka, Harvard Medical School, Boston, Massachusetts, United States
  • Corapi, Kristin M., Harvard Medical School, Boston, Massachusetts, United States
  • Altintas, Mehmet M., Rush University Medical Center, Chicago, Illinois, United States
  • Waikar, Sushrut S., Boston University, Boston, Massachusetts, United States
  • Bianco, Antonio C., University of Chicago Division of the Biological Sciences, Chicago, Illinois, United States
  • Sever, Sanja, Harvard Medical School, Boston, Massachusetts, United States
  • Reiser, Jochen, Rush University Medical Center, Chicago, Illinois, United States

suPAR is an innate-immune derived circulating kidney disease risk factor, elevated plasma levels of which have been associated with diabetic nephropathy. Enzymatic cleavage of domain 1 (D1) from suPAR generates D2D3 fragment. The biological consequence of this fragment is unclear.


1) we used an immunoprecipitation-mass spectrometry to determine the presence of D2D3 fragment in diabetic nephropathy patients with insulin dependence; 2) we generated a transgenic mouse model that drives D2D3 expression from adipocytes with consequent release into circulation. To stimulate D2D3 expression, we treated the control and D2D3 mice with high fat diet (HFD) for 6 months to measure proteinuria monthly. We analyzed the phenotypes of control and D2D3 mice by glucose tolerance test (GTT), glucose stimulated insulin secretion assay (GSIS) in vivo and in vitro; 3) we treated both mouse and human islets with recombinant D2D3 proteins purified from HEK293 cells, and performed in vitro GSIS to determine islet function; 4) we performed immunochemical staining using the control and D2D3 pancreas to explore if D2D3 influences the β-cell mass.


Compared to controls, D2D3 mice with HFD developed significantly increased proteinuria and presented with reduced serum insulin levels. Under chow diet, both in vivo and in vitro GSIS were compromised in D2D3 mice and GTT of these mice was impaired as well. In consistence, isolated islets from WT mice or human pancreas treated with recombinant D2D3 protein displayed impaired response to high dose glucose, as compared to the BSA-treated islets. α-/β-cells distribution pattern was dramatically altered in the D2D3 mice, with glucagon-positive α-cells being randomly dispersed among insulin-positive β-cells. β-cell mass in D2D3 mice was reduced to half of control levels, assessed by the decreased β-cell population in D2D3 islets. Moreover, treatment of mouse β-cell line (MIN6 cells) with D2D3 displayed reduced insulin secretion upon high glucose stimulation and impaired glycolysis and mitochondrial respiration.


Mouse D2D3 fragment regulates glucose homeostasis by playing a direct role in β-cell function. It also impairs podocyte function. Generation of D2D3 represents an inciting event in the immune-derived diabetic kidney disease.


  • NIDDK Support