In the human kidney, ClC-5 is primarily expressed in proximal tubular cells, located in the subapical endosomes, and is involved in the endocytic reabsorption of albumin and LMW proteins. For the first time we demonstrated that ClC-5 is expressed also in podocytes and that it was overexpressed in glomeruli of some proteinuric nephropathies suggesting that proteinuria may play a role in its expression. We also recently discovered that in the human kidney are present 11 different CLCN5 5’UTR isoforms. In particular, isoform A and C are predominantly and exclusively expressed respectively.
To further investigate the role of ClC-5 in proteinuric states, we studied CLCN5 and its 5’UTR isoform expression at mRNA level and ClC-5 protein in renal biopsies of proteinuric nephropathies with different degree of proteinuria: 14 membraneous glomerulopathies (MG) (4,65g/die), 24 LES (3,31g/die), 12 IgA nephropathy (IgAN) (3.02 g/d), 13 diabetic nephropathy (DN) (0.5g/die), and 11 controls. Quantitative comparative RT/PCR and immunocytochemistry were performed.
At mRNA level, we found that CLCN5 was significantly higher in MG (p=0.005) and LES (p=0.002) than in controls and DN. Isoforms A and C were also significantly higher, with major expression of isoform A, showing a direct correlation (r=0.64 p=0.000). The study at protein level was focused on glomerular and tubular compartments and revealed that 1) ClC-5 was significantly higher in IgA (p=0.000) and MG (p=0.034) versus LES both in glomeruli and tubules, 2) tubular and glomerular ClC-5 expression was directly correlated considering all the nephropathies (r=0.59 p=0.000) and 3) proteinuria did not correlate with ClC-5 expression except in LES where it correlated with glomerular expression.
Our study clearly confirms that glomeruli express ClC-5, but also reveals that ClC-5 expression is differently modulated at mRNA and protein level, being proteinuria probably a secondary actor of ClC-5 regulation
