Involvement of the tubular ClC-type exchanger ClC-5 in glomeruli of human proteinuric nephropathies.

UNLABELLED: Glomerular protein handling mechanisms have received much attention in studies of nephrotic syndrome. Histopathological findings in renal biopsies from severely proteinuric patients support the likelihood of protein endocytosis by podocytes. ClC-5 is involved in the endocytosis of albumin in the proximal tubule. AIM: To investigate whether ClC-5 is expressed in the glomerular compartment and whether it has a role in proteinuric nephropathies. ClC-5 expression was studied using Real-time PCR in manually- and laser-microdissected biopsies from patients with type 2 diabetes (n 37) and IgA nephropathy (n 10); in biopsies of membranous glomerulopathy (MG) (n 14) immunohistochemistry for ClC-5 (with morphometric analysis) and for WT1 was done. CONTROLS: cortical tissue (n 23) obtained from unaffected parts of tumor-related nephrectomy specimens. RESULTS: ClC-5 was expressed at glomerular level in all biopsies. Glomerular ClC-5 levels were significantly higher in diabetic nephropaty and MG at both mRNA and protein level (p<0.002; p<0.01). ClC-5 and WT1 double-staining analysis in MG showed that ClC-5 was localized in the podocytes. ClC-5 ultrastructural immunolocalization was demonstrated in podocytes foot processes. Our study is the first to demonstrate that ClC-5 is expressed in human podocytes. The ClC-5 overexpression found in biopsies of proteinuric patients suggests that proteinuria may play a part in its expression and that podocytes are likely to have a key role in albumin handling in proteinuric states.

Early activation of fibrogenesis in transplanted kidneys: a study on serial renal biopsies.

BACKGROUND/AIMS: In kidney transplants, the renin-angiotensin system (RAS) is involved in systemic and local changes that may induce fibrosis. Our aim was to use gene expression and immunohistochemical analysis to investigate the RAS and several factors involved in the fibrogenic cascade in allograft biopsies. METHODS: We considered 43 donor biopsies (T0), 18 biopsies obtained for diagnostic purposes (Td) and 24 protocol biopsies (Tp) taken 2 months after transplantation in patients with stable renal function. Morphometric alpha SMA and TGF beta 1 analysis, and Masson's Trichrome staining were performed. mRNA levels of angiotensinogen, renin, ACE, AT1-R, AT2-R, TGF beta 1, BMP-7, Coll III, fibronectin and alpha SMA were analyzed by real-time RT/PCR. MDRD a year after the transplant was also considered. RESULTS: Significantly higher levels of AT1-R and alpha SMA transcripts were found in Tp than in T0. Regression analysis showed significant TGF beta 1-independent positive correlations between RAS and matrix components in T0 and Tp, but more evident in Tp, where a positive correlation between TGF beta 1 and Masson's Trichrome stained areas was also seen. CONCLUSION: Our results suggest that RAS and TGF beta 1-related fibrogenic loops are activated as early as 2 months after kidney transplantation.

The renal stem cell system in kidney repair and regeneration.

The adult mammalian renal tubular epithelium exists in a relatively quiescent to slowly replicating state, but has great potential for regenerative morphogenesis following severe ischemic or toxic injury. Kidney regeneration and repair occur through three cellular and molecular mechanisms: differentiation of the somatic stem cells, recruitment of circulating stem cells and, more importantly, proliferation/dedifferentiation of mature cells. Dedifferentiation seems to represent a critical step for the recovery of tubular integrity. Dedifferentiation of tubular cells after injury is characterized by the reactivation of a mesenchymal program that is active during nephrogenesis. Epithelial-to-mesenchymal transition (EMT) of renal tubular cells is an extreme manifestation of epithelial cell plasticity. It is now widely recognized as a fundamental process that marks some physiological, such as morphogenesis, as well as pathological events, such as oncogenesis and fibrogenesis. It might be also considered as a key event in the regenerative process of the kidney. Understanding the molecular mechanisms involved in EMT might be useful for designing therapeutic strategies in order to potentiate the innate capacity of the kidney to regenerate.

Pathogenesis of nephrolithiasis: recent insight from cell biology and renal pathology.

Randall's plaques are very common in idiopathic calcium-oxalate nephrolithiasis. These papillary plaques have an apatite mineral structure. While these calcium deposits are generally assumed to be secondary to a purely physico-chemical phenomenon, we advance the hypothesis that they form due to a truly ectopic biomineralization in the renal tissue, and that Henle's loop epithelial cells, or pericyte-like interstitial cells, or papillary stem cells differentiating along a bone lineage might be involved.