Programme

Molecular changes in proximal tubule function in diabetes mellitus

Our studies focus on the changes in the tubulointerstitum (proximal tubule, cortical fibroblast and endothelial cells) that occur when exposed to a `diabetic environment', i.e. high glucose, low density lipoproteins and cytokines implicated in the pathogenesis of diabtic nephropathy. The current discussion focuses on the specific changes in proximal tubule function that occur following exposure to high glucose. In the normal kidney, the proximal tubule plays a crucial role in the reabsorption of 50-70% of the filtered Na⁺ and the receptor mediated uptake of the protein that crosses into the filtrate from the glomerulus. Diabetic nephropathy is frequently associated with increased Na⁺ retention, proteinuria and thickening of the tubular basement membrane is the earliest histological abnormality.

Using experimental models, which include both primary cultures of human proximal tubule (hPTC) cells as well as immortalised cell lines, we found initially that high glucose increases the activity of Na⁺-H⁺ exchanger 3 (NHE3), the key transporter that mediates Na⁺ uptake in the proximal tubule. This increase is paralleled by an increase in the mRNA for NHE3. There is also a similar increase in the activity and protein levels of the V-H⁺-ATPase, which plays a role in HCO₃^- reabsorption. In a recent study we have shown that the activity of NHE3 is upregulated by exposure to albumin. NHE3 and V-H⁺-ATPase are also known to be critical in the endocytosis of albumin, and indeed further studies confirmed that tubular exposure to high glucose increased albumin uptake. These data suggest a possible mechanism linking defective Na⁺ reabsorption and protein handling in the kidney in diabetes mellitus.