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.
Excess levels of protein in urine (proteinuria) is a hallmark of kidney disease that typically occurs in conjunction with diabetes, hypertension, gene mutations, toxins or infections but may also be of unknown cause (idiopathic) 1 . Systemic soluble urokinase plasminogen activator receptor (suPAR) is a circulating factor implicated in the onset and progression of chronic kidney disease (CKD) 2 , such as focal segmental glomerulosclerosis (FSGS) 3,4 . The cellular source(s) of elevated suPAR associated with future and progressing kidney disease is unclear, but is likely extra-renal, as the Reprints and permissions information is available online at
Dysregulation of the actin cytoskeleton in podocytes represents a common pathway in the pathogenesis of proteinuria across a spectrum of chronic kidney diseases (CKD). The GTPase dynamin has been implicated in the maintenance of cellular architecture in podocytes through its direct interaction with actin. Furthermore, the propensity of dynamin to oligomerize into higher-order structures in an actin-dependent manner and to crosslink actin microfilaments into higher order structures have been correlated with increased actin polymerization and global organization of the actin cytoskeleton in the cell. We found that use of the small molecule Bis-T-23, which promotes actin-dependent dynamin oligomerization and thus increased actin polymerization in injured podocytes, was sufficient to improve renal health in diverse models of both transient kidney disease and of CKD. In particular, administration of Bis-T-23 in these renal disease models restored the normal ultrastructure of podocyte foot processes, lowered proteinuria, lowered collagen IV deposits in the mesangial matrix, diminished mesangial matrix expansion and extended lifespan. These results further establish that alterations in the actin cytoskeleton of kidney podocytes is a common hallmark of CKD, while also underscoring the significant regenerative potential of injured glomeruli and that targeting the oligomerization cycle of dynamin represents an attractive potential therapeutic target to treat CKD.
Edited by Xiao-Fan WangPodocyte injury is an early event in diabetic kidney disease and is a hallmark of glomerulopathy. MicroRNA-146a (miR146a) is highly expressed in many cell types under homeostatic conditions, and plays an important anti-inflammatory role in myeloid cells. However, its role in podocytes is unclear. Here, we show that miR-146a expression levels decrease in the glomeruli of patients with type 2 diabetes (T2D), which correlates with increased albuminuria and glomerular damage. miR-146a levels are also significantly reduced in the glomeruli of albuminuric BTBR ob/ob mice, indicating its significant role in maintaining podocyte health. miR-146a-deficient mice (miR-146a
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