A tripartite complex of suPAR, APOL1 risk variants and αvβ3 integrin on podocytes mediates chronic kidney disease

Abstract

Soluble urokinase plasminogen activator receptor (suPAR) independently predicts chronic kidney disease (CKD) incidence and progression. Apolipoprotein L1 (APOL1) gene variants G1 and G2, but not the reference allele (G0), are associated with an increased risk of CKD in individuals of recent African ancestry. Here we show in two large, unrelated cohorts that decline in kidney function associated with APOL1 risk variants was dependent on plasma suPAR levels: APOL1-related risk was attenuated in patients with lower suPAR, and strengthened in those with higher suPAR levels. Mechanistically, surface plasmon resonance studies identified high-affinity interactions between suPAR, APOL1 and αvβ3 integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments αvβ3 integrin activation and causes proteinuria in mice in a suPAR-dependent manner. The synergy of circulating factor suPAR and APOL1 G1 or G2 on αvβ3 integrin activation is a mechanism for CKD.

Association of Serum Soluble Urokinase Receptor Levels With Progression of Kidney Disease in Children

“…For example, suPAR binds to and activates β3-integrins and triggers alterations in podocyte structure and function. 10,25,26 Whether suPAR acts in the tubulointerstitium to promote fibrosis in individuals with congenital anomalies or primary tubulointerstitial diseases requires further study.…”

Predicting Mortality in African Americans With Type 2 Diabetes Mellitus: Soluble Urokinase Plasminogen Activator Receptor, Coronary Artery Calcium, and High‐Sensitivity C‐Reactive Protein

“…[6][7][8] Soluble urokinase plasminogen activator receptor (suPAR) is a marker of immune activation thought to be involved in the pathogenesis of kidney disease; suPAR concentrations have also been associated with mortality and cardiovascular disease in the general population (without comorbidities), in critically ill patients, patients with cerebrovascular disease, HIV infection, and kidney disease. [9][10][11][12][13][14][15][16][17][18][19][20][21] In contrast to hs-CRP, elevated suPAR is reportedly associated with the presence of CAC as well as peripheral arterial disease. 22,23 Whether suPAR levels provide further benefit in risk stratification in African Americans (AA) with T2D has not been studied.…”

Novel Pure αVβ3 Integrin Antagonists That Do Not Induce Receptor Extension, Prime the Receptor, or Enhance Angiogenesis at Low Concentrations

“…One possible reason that the effect is only observed at sub-saturating concentrations of cilengitide is that after binding to αVβ3 and inducing signaling and adoption of the high-affinity ligand-binding state, it releases from the receptor and leaves it unoccupied and in the high-affinity ligand-binding state. 72 A similar mechanism may also limit the ability of partial agonists to treat renal podocyte disorders 18 and supravalvular aortic stenosis in William's syndrome 29 since signaling through αVβ3 may contribute to both of these disorders. Thus, it would be valuable to have high potency pure αVβ3 antagonists to assess whether they offer insights into the pathophysiology of the disorders and/or therapeutic advantages.…”

“…5,6 It plays an important role in bone resorption and has been implicated in contributing to a broad range of pathological processes. These include osteoporosis, 7,8 sickle cell disease vaso-occlusion, [9][10][11] tumor angiogenesis, 6,12 metastasis, 5 tumor-induced bone resorption, 13 herpes simplex and hantavirus viral invasion, [14][15][16] disruption of glomerular barrier function, 17,18 dermal and hepatic fibrosis, [19][20][21][22][23][24] acute myelogenous leukemia, 25 post-cardiac transplant coronary vasculopathy, 26,27 bone resorption by multiple myeloma plasma cells, 28 supravalvular aortic stenosis associated with Williams syndrome, 29 Crohn's disease strictures, 30 and T-cell lymphoma. 31,32 Despite the potential clinical utility of inhibiting αVβ3, there are no approved drugs or biologics targeting this receptor.…”