Advanced glycation end products (AGEs) are a heterogeneous group of protein and lipids to which sugar residues are covalently bound. AGE formation is increased in situations with hyperglycemia (e.g., diabetes mellitus) and is also stimulated by oxidative stress, for example in uremia. It appears that activation of the renin-angiotensin system may contribute to AGE formation through various mechanisms. Although AGEs could nonspecifically bind to basement membranes and modify their properties, they also induce specific cellular responses including the release of profibrogenic and proinflammatory cytokines by interacting with the receptor for AGE (RAGE). However, additional receptors could bind AGEs, adding to the complexity of this system. The kidney is both: culprit and target of AGEs. A decrease in renal function increases circulating AGE concentrations by reduced clearance as well as increased formation. On the other hand, AGEs are involved in the structural changes of progressive nephropathies such as glomerulosclerosis, interstitial fibrosis, and tubular atrophy. These effects are most prominent in diabetic nephropathy, but they also contribute to renal pathophysiology in other nondiabetic renal diseases. Interference with AGE formation has therapeutic potential for preventing the progression of chronic renal diseases, as shown from data of animal experiments and, more recently, the first clinical trials.

Transforming growth factor-β (TGF-β) is a profibrotic cytokine found in chronic renal diseases, which initiates and modulates a variety of pathophysiological processes. It is synthesized by many renal cell types and exerts its biological functions through a variety of signalling pathways, including the Smad and MAPK pathways. In renal diseases, TGF-β is upregulated and induces renal cells to produce extracellular matrix proteins leading to glomerulosclerosis as well as tubulointerstitial fibrosis. Different types of renal cells undergo different pathophysiological changes induced by TGF-β, leading to apoptosis, hypertrophy and abnormalities of podocyte foot processes, which ultimately result in renal dysfunction. In this review, we describe the effects of TGF-β on different renal cell types and the means by which TGF-β participates in the pathomechanisms of glomerular and tubulointerstitial diseases.

The pathophysiology of diabetic nephropathy (DN), one of the most serious complications in diabetic patients and the leading cause of end-stage renal disease worldwide, is complex and not fully elucidated. A typical hallmark of DN is the excessive deposition of extracellular matrix (ECM) proteins in the glomerulus and in the renal tubulointerstitium, eventually leading to glomerulosclerosis and interstitial fibrosis. Although it is obvious that myofibroblasts play a major role in the synthesis and secretion of ECM, the origin of myofibroblasts in DN remains the subject of controversial debates. A number of studies have focused on epithelial-to-mesenchymal transition (EMT) as one source of matrix-generating fibroblasts in the diseased kidney. EMT is characterized by the acquisition of mesenchymal properties by epithelial cells, preferentially proximal tubular cells and podocytes. In this review we comprehensively review the literature and discuss arguments both for and against a function of EMT in renal fibrosis in DN. While the precise extent of the contribution to nephrotic fibrosis is certainly arduous to quantify, the picture that emerges from this extensive body of literature suggests EMT as a major source of myofibroblasts in DN.

One of the major challenges in nephrology is the exponentially growing number of patients developing terminal renal failure. It is now well-appreciated that the majority of these patients have a chronic decline of renal function over years before dialysis is required. This nonspecific process continues even when the initial insult is no longer present and has been called progression of chronic renal disease¹ x 1 Klahr, S., Schreiner, G., and Ichikawa, I. The progression of renal disease. N Engl J Med. 1988; 318: 1657–1666 Crossref | PubMed | Google Scholar See all References . Regardless of the primary cause, the common underlying histologic lesions comprise tubulointerstitial fibrosis, tubular atrophy, and glomerulosclerosis¹ x 1 Klahr, S., Schreiner, G., and Ichikawa, I. The progression of renal disease. N Engl J Med. 1988; 318: 1657–1666 Crossref | PubMed | Google Scholar See all References ^,2 x 2 Brenner, B.M. Remission of renal disease: Recounting the challenge, acquiring the goal. J Clin Invest. 2002; 110: 1753–1758 Crossref | PubMed | Google Scholar See all References . Clinical studies have provided ample evidence that hypertension and the degree proteinuria are the most important factors influencing progression³ x 3 Campbell, R.C., Ruggenenti, P., and Remuzzi, G. Halting the progression of chronic nephropathy. J Am Soc Nephrol. 2002; 13: S190–S195 Crossref | PubMed | Google Scholar See all References . The role of these mechanisms in progression of chronic nephropathy has been reviewed elsewhere³ x 3 Campbell, R.C., Ruggenenti, P., and Remuzzi, G. Halting the progression of chronic nephropathy. J Am Soc Nephrol. 2002; 13: S190–S195 Crossref | PubMed | Google Scholar See all References . Angiotensin II (Ang II) mediates both hemodynamic changes and renal growth suggesting that these processes are intimately connected. Both are thought to contribute to progression⁴ x 4 Wolf, G., Butzmann, U., and Wenzel, U.O. The renin-angiotensin system and progression of renal disease: From hemodynamics to cell biology. Nephron Physiol. 2003; 93: P3–P13 Crossref | PubMed | Scopus (126) | Google Scholar See all References . As summarized in Table 1 Table 1 , the nonhemodynamic actions of Ang II include stimulation of tubular transport, facilitation of proteinuria by modifying structure and function of the glomerular ultrafiltration barrier, induction of proinflammatory as well as profibrogenic cytokines such as transforming growth factor-β (TGF-β) (for review see⁴ x 4 Wolf, G., Butzmann, U., and Wenzel, U.O. The renin-angiotensin system and progression of renal disease: From hemodynamics to cell biology. Nephron Physiol. 2003; 93: P3–P13 Crossref | PubMed | Scopus (126) | Google Scholar See all References ). Therefore, antagonizing these effects of Ang II is a key component of therapeutic strategies to halt progression.

Inhibitors of the renin-angiotensin-aldosterone system attenuate glomerulosclerosis and interstitial fibrosis. Although the mechanisms underlying their antifibrotic effects are complex, angiotensin II (Ang II) emerges as a major profibrogenic cytokine. Ang II modulates renal cell growth, extracellular matrix synthesis, and degradation by multiple fibrotic pathways. One of the main targets of Ang II in renal fibrosis is TGFβ. Many, but not all, of the stimulatory effects of Ang II on fibrogenesis depend on the induction of TGFβ and its downstream mediators of matrix accumulation, inflammation, and apoptosis. However because of the difficulty in targeting TGFβ, connective tissue growth factor β (CTGF), a downstream mediator of TGFβ, has become a more promising antifibrotic target. Ang II can directly induce expression of renal CTGF and mediate epithelial-mesenchymal transition. Other profibrotic factors stimulated by Ang II include endothelin-1, plasminogen activator inhibitor-1, matrix metalloproteinase (MMP)-2, and a tissue inhibitor of metalloproteinase-2. Finally, connections among Ang II, hypoxia, and the induction of hypoxia-inducible factor-1α contribute to fibrogenesis. A better understanding of the multiple morphogenic effects of Ang II may be necessary to develop better strategies to halt the progression of renal disease.