Urinary tumor necrosis factor contributes to sodium retention and renal hypertrophy during diabetes

Abstract

Nephropathy is a major contributor to overall morbidity and mortality in diabetic patients. Early renal changes during diabetes include Na retention and renal hypertrophy. Tumor necrosis factor (TNF) is elevated during diabetes and is implicated in the pathogenesis of diabetic nephropathy. We tested the hypothesis that TNF contributes to Na retention and renal hypertrophy during diabetes. Rats with streptozotocin-induced diabetes exhibit increased urinary TNF excretion, Na retention, and renal hypertrophy through the first 20 days of diabetes. Administration of a soluble TNF antagonist (TNFR:Fc) to diabetic rats reduces urinary TNF excretion and prevents Na retention and renal hypertrophy. TNF stimulates Na uptake in distal tubule cells isolated from diabetic rats, providing a possible mechanism for TNF-induced Na retention. We conclude that urinary TNF contributes to early diabetic nephropathy and may serve as a valuable diagnostic marker. Furthermore, inhibition of TNF during diabetes may attenuate early pathological changes in diabetic nephropathy.

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

“…There was an increase in urinary flow in the diabetic animals in this study compared with the control animals, in agreement with other studies; this is probably induced by an osmotic effect of the high glucose concentration in tubular lumen and increased glomerular filtration rate (GFR) observed in the DM group (DiPetrillo et al. 2003; Rebsomen et al. 2006; Dronavalli et al.…”

The Role of Inflammatory Cytokines in Diabetic Nephropathy

“…86 Experimental studies have consistently reported that mRNA encoding TNF-␣ and protein levels increase in glomerular and proximal tubule cells from diabetic rats. 45,73,74,[87][88][89] These investigations demonstrated a significant role of TNF-␣ in the development of renal hypertrophy and hyperfunction, two main alterations during the initial stage of diabetic nephropathy. 88,89 TNF-␣ has a stimulatory effect on sodium-dependent solute uptake in cultured mouse proximal tubular cells, 90 and in those studies diabetic rats exhibited enhanced urinary TNF-␣ excretion, sodium retention, and renal hypertrophy, which were prevented by administration of the anti-TNF-␣ agent TNFR:Fc, a soluble TNF-␣ receptor fusion protein.…”

“…45,73,74,[87][88][89] These investigations demonstrated a significant role of TNF-␣ in the development of renal hypertrophy and hyperfunction, two main alterations during the initial stage of diabetic nephropathy. 88,89 TNF-␣ has a stimulatory effect on sodium-dependent solute uptake in cultured mouse proximal tubular cells, 90 and in those studies diabetic rats exhibited enhanced urinary TNF-␣ excretion, sodium retention, and renal hypertrophy, which were prevented by administration of the anti-TNF-␣ agent TNFR:Fc, a soluble TNF-␣ receptor fusion protein. 89,90 In addition to these data on renal hypertrophy and hyperfunction, mRNA levels and urinary TNF-␣ concentrations in the renal cortex directly and independently correlate with urinary albumin excretion.…”

Determination of oxidative stress and cellular inflammation in patients with diabetic nephropathy and non-diabetic nephropathy being administered hemodialysis treatment due to chronic renal failure

“…16 TNF-a is suggested to be contributing to renal hypertrophy and sodium retention as significant renal modifications which occur during the beginning of DN. 17 As well as cytokines, neopterin level response also is accepted to be a non-specific biochemical marker of the evoked cellular immune response. Measurement of neopterin level gives an idea about the degree of activation of cellular inflammation as in vivo.…”