Sodium Restriction Decreases AP-1 Activation after Nephron Reduction in the Rat: Role in the Progression of Renal Lesions

Abstract

Renal hyperplasia and hypertrophy are early events after nephron reduction which precede progressive destruction of the remnant kidney. Restriction of dietary sodium content was shown to reduce renal lesions following nephron reduction. AP-1 is a transcription factor, resulting from heterodimerization of fos and jun proteins, which mediates the effects of mitogenic growth factors. To elucidate the role of AP-1 in growth processes involved in renal deterioration, we evaluated whether restriction of dietary sodium content (0.25 vs. 0.50% sodium w/w) affected AP-1-DNA binding and hyperplasia in the remnant kidney after nephron reduction (70% nephrectomy). Cell proliferation, evaluated by PCNA immunostaining, increased progressively from day 7 to day 60 in glomeruli, proximal and distal tubules and loops of Henle of nephrectomized (Nx) rats compared to control sham-operated (C) animals. AP-1-DNA binding activity increased 7 and 14 days after surgery, but it was reduced below C values at day 60. c-fos and c-jun expression were also reduced in Nx rats at day 60. Sodium restriction significantly reduced the number of PCNA-stained cells in glomeruli and tubules at days 14 and 60, but not at day 7, whereas it decreased AP-1 activation at all times of the study. This effect was associated to a marked reduction of renal lesions in Nx rats. In conclusion, we showed that, after nephron reduction, the beneficial effect of sodium restriction was associated with a reduction of hyperplasia and AP-1 activation, but that the latter did not parallel delayed cell proliferation rate in remaining nephrons. Thus, we propose that different transduction pathways are involved in cell proliferation after nephron reduction, according to the time of evolution of renal lesions.

JunD protects against chronic kidney disease by regulating paracrine mitogens

“…Moreover, several experimental and clinical observations suggest that cell proliferation plays a key role in the destruction of kidneys during chronic disease. First, proliferation of mesangial, tubular, and interstitial cells increases in many renal diseases and correlates with the severity of renal lesions (2)(3)(4)(5). Secondly, we have shown that the development of renal lesions parallels the extent of cell proliferation in two mouse strains (FVB/N and C57Bl6 × DBA2/F1) and in two experimental models (unilateral and subtotal nephrectomy) that respond differently to nephron loss (3,26).…”

“…Subtotal nephrectomy induces the expression of c-fos and c-jun genes, cell proliferation, and renal lesions (3). Interfering with the development of renal lesions (either by dietary or by pharmacological modulations) decreases both AP-1 activity and cell proliferation in several experimental models of chronic renal injury (5,(18)(19)(20). Taken together, these results suggest that AP-1 could be a major determinant in the development of renal lesions.…”

“…The EGF pathway acts as an autocrine/ paracrine system in the kidney; distal tubular cells secrete the ligands (predominantly EGF and TGF-α), whereas the receptor (EGFR) is abundantly expressed in proximal tubules (31,32). We showed previously the central role of this pathway in renal deterioration (5,9). Hence, we monitored the expression of EGF and TGF-α 60 days after nephron reduction in JunD -/-mice and wild-type littermates using RPA.…”

“…In some cases, this compensatory process becomes pathological with the development of renal lesions and end-stage renal failure (1). Although the pathophysiology of compensation and progression is complex, deregulated proliferation of glomerular, tubular, and interstitial cells may promote the development of progressive glomerular sclerosis, tubular cysts, and interstitial fibrosis (2)(3)(4)(5). Indeed, the reduction of renal cell proliferation, using pharmacological growth factor inhibitors (6), neutralizing Ab's (7), antisense oligonucleotides (8), or transgenic strategies (9), halts the progression of renal lesions in some experimental models of renal injury.…”

Targeted expression of a dominant-negative EGF-R in the kidney reduces tubulo-interstitial lesions after renal injury

“…Since EGF is a potent mitogen for renal tubular cells (6, 7) and a relationship between cell proliferation and tubular lesions has been suggested after nephron reduction (40), PCNA immunostaining was performed on kidney sections from transgenic and wild-type animals. In wild-type mice, the number of tubular PCNA-positive cells was slightly higher in remnant kidneys of nephrectomized mice, as compared with shamoperated animals, 8 months after surgery ( Table 2).…”