Renal uptake of the antiapoptotic protein survivin is mediated by megalin at the apical membrane of the proximal tubule

Abstract

The inhibitor of apoptosis protein survivin is a bifunctional molecule that regulates cellular division and survival. We have previously shown that survivin protein can be found at high concentrations in the adult kidney, particularly in the proximal tubules. Here, survivin is localized primarily at the apical membrane, a pattern that may indicate absorption of the protein. Several proteins in primary urine are internalized by megalin, an endocytosis receptor, which is in principle found in the same localization as survivin. Immunolabeling for survivin in different species confirmed survivin signal localizing to the apical membrane of the proximal tubule. Immunoelectron microscopy also showed apical localization of survivin in human kidneys. Furthermore, in polarized human primary tubular cells endogenous as well as external recombinant survivin is stored in the apical region of the cells. Costaining of survivin and megalin by immunohistochemistry and immunoelectron microscopy confirmed colocalization. Finally, by surface plasmon resonance we were able to demonstrate that survivin binds megalin and cubilin and that megalin knockout mice lose survivin through the urine. Survivin accumulates at the apical membrane of the renal tubule by reuptake, which is achieved by the endocytic receptor megalin, collaborating with cubilin. For this to occur, survivin will have to circulate in the blood and be filtered into the primary urine. It is not known at this stage what the functional role of tubular survivin is. However, a small number of experimental and clinical reports implicate that renal survivin is important for functional integrity of the kidney.

Alpha8 Integrin (Itga8) Signalling Attenuates Chronic Renal Interstitial Fibrosis by Reducing Fibroblast Activation, Not by Interfering with Regulation of Cell Turnover

“…Surprisingly, the mRNA expression of survivin was increased, but survivin protein was reduced by UUO, irrespective of the mouse genotype. This might be due to the fact that survivin protein is primarily regulated via tubular uptake from the primary urine and not via expression by renal cells [ 18 ].…”

Megalin and cubilin in proximal tubule protein reabsorption: from experimental models to human disease

“…105 In addition, megalin has been shown to mediate the uptake of endogenous substances that may be involved in modulation of and recovery from AKI, [106][107][108] including NGAL 109 and survivin. 110 So far no studies have established the functional importance of either megalin or cubilin for the progression of AKI. It is, however, intriguing that changes in megalin expression have been identified in a time-dependent manner in AKI, leading to the speculation that megalin may play a dual role in AKI, initially being involved in progression but, with time, eventually also playing a role in recovery by the clearance of cellular debris and tubular, endocytic uptake of filtered substances, such as NGAL, important for cellular protection.…”

Megalin in acute kidney injury: foe and friend

“…NGAL has been shown to bind megalin (32), and the localization of filtered NGAL in late endosomes and lysosomes during I/R in mice suggests that megalin mediates uptake into PTECs (53,56) and thus is important for the observed renoprotective effect. Other proteins that have been shown to bind to megalin, such as L-FABP, clusterin, and survivin (34,42,63), may also have renoprotective effects in AKI. This has been demonstrated in L-FABP-overexpressing mice exposed to ischemia, cisplatin, or aristolochic acid (51,59,92).…”

“…Survivin is expressed in the heart, brain, liver, lung, and kidney, where it regulates cell division and survival (2). Filtered survivin binds to megalin, mediating proximal tubule uptake (34), and is also known to be expressed in PTECs under normal physiological conditions (46). Studies using kidney-specific survivin deletion have shown that survivin increases the functional and structural recovery of PTECs after I/R injury in mice (14) and reduces tubular injury (39) in cisplatin-induced AKI.…”