Polyol pathway in diabetic nephropathy

Aldose reductase (polyol formation) pathway

1. The polyol pathway involves two enzymatic reactions.
2. The first is the reduction of glucose to sorbitol by the action of aldose reductase.
3. The second is the oxidation of sorbitol to fructose by the action of sorbitol dehydrogenase. 
4. In the aldose reductase reaction, NADPH is oxidised to NADP+ as glucose is converted to sorbitol.
5. NADP+ is converted back to NADPH by the pentose phosphate pathway (PPP).
6. PPP contributes to the triose phosphate pool.
7. In the sorbitol dehydrogenase reaction, NAD+ is reduced to NADH as sorbitol is reduced to fructose. 
8. High NADH:NAD+ ratio inhibits formation of 1,3-BPG (or 1,3-DPG).
9. http://en.wikipedia.org/wiki/Polyol_pathway
10. Also called the sorbitol-aldose reductase pathway.

Complications of diabetes: Diabetic nephropathy 

1. The polyol pathway appears to be implicated in diabetic complications, especially in microvascular damage to the retina, kidney, and nerves.
2. In diabetic renal complications, hyperglycemia may cause damage at a cellular level in both glomerular and tubular locations, often preceding overt dysfunction.
3. Sorbitol cannot cross cell membranes, and, when it accumulates, it produces osmotic stresses on cells by drawing water into the insulin-independent tissues, resulting in oedematous tissues.

Aldose reductase and the role of the polyol pathway in diabetic nephropathy

A possible cause of hyperfiltration and glomerular dysfunction in diabetes is: aldose reductase-induced use of nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) drives the pentose phosphate pathway, which culminates in a protein kinase C–induced increase in glomerular prostaglandin production and loss of mesangial cell contractility.

In diabetes, hyperglycemia-induced renal polyol pathway activity does not occur in isolation but instead in tandem with oxidative changes and the production of reactive dicarbonyls and ,-unsaturated aldehydes. Aldose reductase may detoxify these compounds.

In renal mesangial and proximal tubule cells, the accumulation of sorbitol can be demonstrated by elevated glucose concentrations; its accumulation has been proposed as a mechanism for altered cellular myoinositol level and reduced Na+/K+-ATPase activity, each with a potentially detrimental effect in diabetes. However, in the cells of the inner medulla, sorbitol may function, together with betaine and glycerophosphorylcholine, as part of the organic osmolyte defense against extracellular solute fluctuations.

Fructose

Fructose, the second product of polyol pathway is increased several fold in tissues with an activated polyol pathway and can contribute to nonenzymic fructosylation of proteins and provide 3-deoxyglucosone, the precursor to advanced glycation end products (AGEs).

After formation of polyol pathway products, important alterations in the ratio of reduced pyridine nucleotides result from flux through the polyol pathway.

Sorbitol

Reduction of glucose to sorbitol uses NADPH and oxidation of sorbitol increases NADH with a resultant rapid change in the cytoplasmic redox state. Decreased NADPH (altered cytosolic ratio of NADPH:NADP+) may compromise reduction of glutathione in oxidatively stressed cells. Increased formation of NADH, following oxidation of sorbitol to fructose, favors a condition of hyperglycemia-induced pseudohypoxia in diabetic tissue whereby abnormalities accompanying the increase in the ratio of NADH:NAD+, without a decrease in pO2, bear close parallels to the effects of true hypoxia on vascular function.

NADPH:NADP+ ratio; NADH:NAD+ ratio; PPP

Increased use of NADPH by activity of aldose reductase could alter cellular metabolism in several ways, consequent in part on the stimulation provided to the pentose phosphate pathway. As the oxidative reactions of the pentose phosphate pathway are inhibited by NADPH, its consumption in aldose reductase–activated conversions provides the conditions for a constant throughput of glucose to provide pentose phosphate pathway intermediates. Flux through the pentose phosphate pathway may be favored further if an increased NADH:NAD+ ratio inhibits the NAD+-requiring enzyme glyceraldehyde-3-phosphate dehydrogenase, preventing 1,3-bisphosphoglycerate formation from glyceraldehyde-3-phosphate in glycolysis.

Diagram

These pathways are summarized in Figure 1. In part, activation of the pentose phosphate pathway supplies the increased requirements for ribose 5-phosphate and NADPH for biosynthetic reactions occurring with renal hypertrophy in experimental diabetes.

Polyol pathway in hyperglycaemia

The effect of the polyol pathway on pyridine nucleotide flux and metabolism of glucose. The metabolism of glucose to sorbitol and fructose in the polyol pathway by aldose reductase (AR) and sorbitol dehydrogenase (SDH), respectively, alters cytosolic pyridine nucleotides to provide an increased ratio of NADP+/NADPH and NADH/NAD+. Utilization of NADPH provides conditions for sustained action of the pentose phosphate pathway (PPP) whereas use of NAD+ may inhibit formation of 1, 3 bisphosphoglycerate (1,3 BPG) from glyceraldehyde-3-phosphate resulting in an increased triose phosphate pool. HK, hexokinase.

Source:
Kidney International. Direct Effects Of High Glucose. Available at: http://www.nature.com/ki/journal/v58/n77s/fig_tab/4491969f1.html#figure-title (Accessed 30 May 2013)

Citation:
Marjorie Dunlop. Aldose reductase and the role of the polyol pathway in diabetic nephropathy. Kidney International (2000) 58, S3–S12; doi:10.1046/j.1523-1755.2000.07702.x

Correspondence:
Marjorie Dunlop, Ph.D., University of Melbourne, Department of Medicine, Royal Melbourne Hospital, Grattan Street, Parkville, Victoria 3050, Australia. E-mail: m.dunlop@medicine.unimelb.edu.au