Progression and regression in renal vascular and glomerular fibrosis

Abstract

End-stage renal disease (ESRD) is characterized by the development of fibrotic lesions in the glomerular, interstitial and vascular compartments. Renal fibrogenesis, a common complication of diabetes and hypertension, is a complex dynamic process involving several players such as inflammatory agents, cytokines, vasoactive agents and enzymes participating in extracellular matrix assembly, anchoring or degradation. The only available treatment today against chronic renal failure is dialysis or kidney transplantation, making thus ESRD one of the most expensive diseases to treat on a per-patient basis. An emerging challenge for clinicians, maybe the nephrologist's Holy Grail in the 21st century, is to stop definitively the decline of renal function and, if possible, to achieve regression of renal fibrosis and restoration of renal structure. Over the last 5 years, different approaches have been tested in experimental models of nephropathy with variable degree of success. In this review, we will focus on the mechanisms of the hypertension-associated fibrosis and the few recent studies that gave promising results for a therapeutic intervention.

Figure 1

Classically, the development of renal fibrosis of vascular origin was considered as an adaptive response to blood pressure increase. This notion has been challenged lately by the concept that vasoactive agents can control extracellular martrix synthesis through a genetic action independent of their constrictor effects.

Figure 2

Antagonism of angiotensin II action inhibited collagen I gene activation within the renal vasculature (glomeruli and afferent arterioles) and prevented the development of glomerulosclerosis without normalizing systolic pressure increase (Boffa et al. 1999).

Figure 3

Angiotensin II-induced signalling pathways that lead to activation of collagen I gene. Interruption of one of these cascades is sufficient to inhibit collagen I synthesis and to prevent the development of fibrosis (dash arrows indicate the targets used in experimental studies to block collagen I formation).

Figure 4

Chronic inhibition of nitric oxide is accompanied by the development of renal failure as evidenced by the increase of urinary protein excretion, plasma creatinine and the exaggerated extracellular matrix accumulation in renal cortex. Treatment of the diseased animals with an angiotensin receptor antagonist normalized renal functional and structural parameters indicating that renal fibrosis is a reversible phenomenon, at least in this experimental model (white, black and grey bars represent control animals and animals treated for 4 weeks with L-NAME or 4 weeks with L-NAME followed by 4 weeks L-NAME + losartan, respectively; L-NAME: a NO synthase inhibitor; Los: losartan, an AT1 receptor antagonist; w: weeks (Boffa et al. 2003).

Figure 5

Factors controlling the formation of extracellular matrix and the development of renal vascular and glomerular fibrosis. Inhibition of pro-fibrogenic agents and/or activation of anti-fibrogenic systems have been accompanied by regression of fibrosis and restoration of renal function in experimental nephropathies.