Effect of Proteinuria on Cellular Expression of the Cubilin-Amnionless CUBAM Endocytic Complex

Albumin is protein filtered by the glomerulus and subsequently reabsorbed in the proximal tubule. Reabsorption is mediated at least in part by cubilin-amnionless (cubam) endocytic receptor complex. Proteinuria is an important renal biomarker correlated with the poor prognosis of the kidney disease. However, expression of the cubam complex is not well studied in disease. These studies aimed to investigate the expression and turnover of the cubam complex in proteinuria and the effect of matrix metalloproteinase inhibition on the expression of the cubam complex.In a mouse model of protein overload proteinuria, cubam complex was significantly reduced in the proximal tubule associated with a rise of urinary shedding of both cubilin and amnionless. An increase in renal matrix metalloprotease activity in proteinuria accompanies the urinary loss of these receptors. Furthermore, matrix metalloprotease inhibition (MMPI) treatment has an antiproteinuric effect by reducing urinary proteins excretion in proteinuric animals. Similarly, MMPI ameliorated cubam endocytic complex shedding in the urine. In addition, the studies investigated the degree of tubulointerstitial injury in experimental animals finding an increase in renal proinflammatory cytokines, inflammatory cell infiltration, collagen and apoptosis in proteinuria reversed by MMPI. Moreover, cubam complex expression was significantly downregulated in the proximal tubules of the patients with minimal change disease (MCD), membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS), consistent with the findings in the mouse models.In conclusion, this indicates a renoprotective action of MMPI in proteinuric nephropathies. This may have important clinical implications in the therapeutic approach to proteinuria.