Date of Award
Doctor of Philosophy (PhD)
Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD), where prolonged exposure to hyperglycemia induces damage to proximal tubule cells of the kidney. Since progression to ESRD correlates to pathological changes in the tubular segments of the kidney, the effects of hyperglycemia in the PT portion of the nephron may be particularly relevant to the progression of DN. Development of this disease also is likely to occur in the context of exposure to other renal toxins, and the heavy metal cadmium (Cd2+) may be the most relevant due to the accumulation of this metal in the major cell type involved in glucose reabsorption: proximal tubule cells. Preliminary microarray analysis has shown human proximal tubule (HPT) cells exposed acutely and chronically to Cd2+ have an increased expression of an aldose reductase (AR) isoform, AKR1B10. This isoform along with AKR1B1 and sorbitol dehydrogenase (SORD) are involved in glucose metabolism under hyperglycemic conditions via the polyol pathway. The goal of this study was to verify and extend these observations in culture of HPT cells. For this purpose, HPT cells were exposed to one of the three following treatments; 5.5 (control), 7.5, 11, or 16 mM glucose concentrations for 8 days; 9, 27, 45 Î¼M Cd2+ for 24 hours (acute), or 4.5, 9, 27 Î¼M Cd2+ for 13 days (chronic). Real-time PCR was used to measure the expression level of these enzymes. Exposures to either hyperglycemia or Cd2+ stimulated a significant induction of AKR1B10 in HPT cells; however, exposure to these renal toxins had no effect on AKR1B1 or SORD expression. We also observed glucose-induced loss of epithelial morphology that correlated to an induction of N- Cadherin (CDH2), a mesenchymal marker. These results are suggestive of potential synergistic effects of Cd2+ and hyperglycemia in the toxic responses of the proximal tubules during the development of DN.
Davis, Bethany Anne, "The Involvement Of Polyol Pathway In Hypgerglycemia And Cadmium Toxicity In The Establishment Of Diabetic Neprhopathy" (2018). Theses and Dissertations. 2196.