Cutillas, Pedro Rodriguez; (2004) Application of mass spectrometry and proteomics to study kidney function; The concept of renal intracrine regulation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The accepted view on hormonal regulation of renal function is that hormones operating on the basolateral side of renal tubular cells control the expression, localisation and activity of proteins involved in key renal functions. The studies presented in this thesis aimed at the exploration of the idea that bioactive peptides present in the tubular fluid (or 'pre-urine') may also have a role in controlling renal tubular cell function. To this end, urine from renal Fanconi syndrome (FS) patients was analysed and compared with that of normal individuals. In addition, the protein composition of apical and basolateral membranes from rat renal tubular cells was also investigated. Methods for the extraction of polypeptides from urine were investigated. Implementation of these methods for the analysis of FS urine (with emphasis on Dent's disease) gave insights into the nature of low molecular weight proteinuria and suggested that the reuptake of proteins from the glomerular filtrate shows some kind of specificity and it is not as promiscuous as previously thought. In addition to plasma proteins, numerous peptides with previously reported bioactive actions were detected in both normal and FS urine, although the relative abundance of these peptides was altered in FS patients. In a separate set of experiments, several proteins with potential roles in signal transduction were found in apical membrane segments of renal tubular cells. The presence of bioactive peptides in Dent's and normal urine and the finding that proteins with signalling roles are located on apical membranes support the notion of an intracrine system operating in the lumen of the healthy tubules. It is concluded that an alteration on the hormonal composition of the tubular fluid, as in diseases that lead to proteinuria, may contribute to the progression of these diseases with the end result of renal dysfunction and ultimately kidney failure.

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