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Correlative histochemical studies on preneoplastic and neoplastic lesions in the kidney of rats treated with
Abstract:
Renal tubular lesions induced in male rats by two different carcinogens, N-nitrosomorpholine (NNM) and N-ethyl-N-hydroxyethylnitrosamine (EHEN), using a limited exposure "stop" protocol were investigated histochemically to demonstrate phenotypic cellular changes. The parameters measured included basophilia, glycogen content and the activity of the enzymes glucose-6-phosphatase (G6PASE), glycogen synthetase (SYN), glycogen phosphorylase (PHO), glucose-6-phosphate dehydrogenase (G6PDH), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), succinate dehydrogenase (SDH), alkaline phosphatase (ALP), acid phosphatase (ACP) and gamma-glutamyl transpeptidase (gamma-GT). The lesions observed were predominantly of either basophilic or oncocytic types. In each case, tubular lesions (altered tubules) appeared to give rise to epithelial tumors (epitheliomas) with the same cellular phenotype. Basophilic tubules and epitheliomas proved to be strongly positive for GAPDH and G6PDH while demonstrating a reduction or loss of G6PASE, ALP, ACP, gamma-GT, and SDH compared with controls and the surrounding proximal or distal tubules. In addition, large basophilic epitheliomas demonstrated an increase in both SYN and PHO activities. In contrast, most oncocytic tubules and oncocytomas characterized by abundant densely granular cytoplasm showed a reduction in the activity of G6PDH, but were intensely positive for SDH. However, a few oncocytic lesions demonstrated a decrease in both SDH and G6PDH activity. Rarely, decreased SDH and elevated G6PDH activities were observed in altered tubules resembling oncocytic tubules. It remains to be clarified whether these tubules represent a variation of the oncocytic lesions or, perhaps, another type of tubular lesion. The results indicate that basophilic and oncocytic epithelial tumors differ in their cytochemical pattern and histogenesis. In line with earlier suggestions, the basophilic tumors apparently originate from the proximal renal tubules, while the oncocytomas develop from the distal parts of the nephron. The basophilic tumors are characterized by an increased pentose phosphate pathway and glycolysis, with a corresponding reduction in mitochondrial respiration. However, the majority of the oncocytomas show an increased activity of the mitochondrial enzyme SDH, and a marked decrease in the activity of the key enzyme of the pentose phosphate pathway.
Insights
This study investigated renal tubular lesions in rats, revealing distinct histochemical patterns for basophilic and oncocytic tumors. Basophilic tumors show altered glycolysis and pentose phosphate pathway activity, while oncocytic tumors exhibit different enzyme profiles, suggesting different origins.
Area of Science:
- Renal pathology
- Carcinogenesis
- Enzymology
Background:
- Carcinogens N-nitrosomorpholine (NNM) and N-ethyl-N-hydroxyethylnitrosamine (EHEN) induce renal tubular lesions in rats.
- These lesions can progress to epithelial tumors (epitheliomas) with distinct cellular phenotypes.
Purpose of the Study:
- To histochemically investigate phenotypic cellular changes in renal tubular lesions induced by NNM and EHEN.
- To differentiate the cytochemical patterns and histogenesis of basophilic and oncocytic renal tumors.
Main Methods:
- Male rats were exposed to NNM or EHEN using a limited "stop" protocol.
- Histochemical analysis was performed to measure glycogen content and the activity of key enzymes involved in glycolysis, pentose phosphate pathway, and mitochondrial respiration.
- Enzymes analyzed included glucose-6-phosphatase (G6PASE), glycogen synthetase (SYN), glycogen phosphorylase (PHO), glucose-6-phosphate dehydrogenase (G6PDH), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), succinate dehydrogenase (SDH), alkaline phosphatase (ALP), acid phosphatase (ACP), and gamma-glutamyl transpeptidase (gamma-GT).
Main Results:
- Two predominant lesion types were observed: basophilic and oncocytic.
- Basophilic tubules and epitheliomas showed increased GAPDH and G6PDH, decreased G6PASE, ALP, ACP, gamma-GT, and SDH, with elevated SYN and PHO in larger tumors.
- Oncocytic tubules and oncocytomas typically exhibited reduced G6PDH and elevated SDH, though some variations were noted.
Conclusions:
- Basophilic and oncocytic renal tumors exhibit distinct cytochemical profiles and histogenesis.
- Basophilic tumors likely originate from proximal renal tubules, characterized by enhanced glycolysis and pentose phosphate pathway activity.
- Oncocytic tumors appear to develop from distal nephron segments, with a predominant increase in mitochondrial succinate dehydrogenase activity.