No abstract

All progressive renal diseases are the consequence of a process of destructive fibrosis. This review will focus on tubulointerstitial fibrosis, the pathophysiology of which will be divided into four arbitrary phases. First is the cellular activation and injury phase. The tubules are activated, the peritubular capillary endothelium facilitates migration of mononuclear cells into the interstitium where they mature into macrophages, and myofibroblasts/activated fibroblasts begin to populate the interstitium. Each of these cells releases soluble products that contribute to ongoing inflammation and ultimately fibrosis. The second phase, the fibrogenic signaling phase, is characterized by the release of soluble factors that have fibrosis-promoting effects. Several growth factors and cytokines have been implicated, with primary roles suggested for transforming growth factor-beta, connective tissue growth factor, angiotensin II and endothelin-1. Additional factors may participate including platelet-derived growth factor, basic fibroblast growth factor, tumor necrosis factor-alpha and interleukin-1, while interferon-gamma and hepatocyte growth factor may elicit antifibrotic responses. Third is the fibrogenic phase when matrix proteins, both normal and novel to the renal interstitium, begin to accumulate. During this time both increased matrix protein synthesis and impaired matrix turnover are evident. The latter is due to the renal production of protease inhibitors such as the tissue inhibitors of metalloproteinases and plasminogen activator inhibitors which inactivate the renal proteases that normally regulate matrix turnover. Fourth is the phase of renal destruction, the ultimate sequel to excessive matrix accumulation. During this time the tubules and peritubular capillaries are obliterated. The number of intact nephrons progressively declines resulting in a continuous reduction in glomerular filtration.

Monocyte-derived macrophages can determine the outcome of the immune response and whether this response contributes to tissue repair or mediates tissue destruction. In addition to their important role in immune-mediated renal disease and host defense, macrophages play a fundamental role in tissue remodeling during embryonic development, acquired kidney disease, and renal allograft responses. This review summarizes macrophage phenotype and function in the orchestration of kidney repair and replacement of specialized renal cells following injury. Recent advances in our understanding of macrophage heterogeneity in response to their microenvironment raise new and exciting therapeutic possibilities to attenuate or conceivably reverse progressive renal disease in the context of fibrosis. Furthermore, parallels with pathological processes in many other organs also exist.Nonstandard abbreviations used: AT1, angiotensin II receptor type 1; MCP-1, monocyte chemoattractant protein 1; SHIP, Src homology 2-containing inositol-5′-phosphatase; Ym-1, chitinase 3-like 3.

These studies establish an important fibrogenic role for PAI-1 in the renal fibrogenic response. The results demonstrate that one important fibrosis-promoting function of PAI-1 is its role in the recruitment of fibrosis-inducing cells, including myofibroblasts and macrophages.

No abstract

Rats with significant proteinuria induced by daily injections of bovine serum albumin develop interstitial inflammation and fibrosis. The present study was designed to investigate the molecular basis of interstitial monocyte (Mø) recruitment and early interstitial fibrosis. Groups of rats were sacrificed after one, two and three weeks. Despite an increase in interstitial Mø at week 1, whole kidney mRNA levels were not elevated for monocyte chemoattractant protein-1 (MCP-1), osteopontin or vascular cell adhesion molecule-1 (VCAM-1). Only osteopontin mRNA levels were significantly elevated in the renal cortex at four days. At two and three weeks, MCP-1 and osteopontin mRNA levels were increased and the proteins showed distinct tubular patterns of distribution. By immunostaining increased expression of VCAM-1 and intercellular adhesion molecule-1 (ICAM-1) was restricted to their presence or the surface of the interstitial inflammatory cells. TGF-beta 1 mRNA levels were increased at weeks 1, 2 and 3 (2.1, 2.9, 3.6x); interstitial and occasional cortical tubular cells expressed TGF-beta 1 mRNA and protein. There was a progressive rise in the number of cortical interstitial fields with increased staining for collagen (col) 1 (18, 29, 44%), col III (39, 61, 63%), col IV (7, 13, 29%), laminin (4, 10, 30%), fibronectin (14, 28, 37%), tenascin (19, 22, 14%) and in total renal col measured biochemically (1.1, 1.4, 2.0x) at weeks 1, 2 and 3, respectively. Renal matrix protein mRNA levels were variable and not always predictive of fibrosis. Only col I and tenascin levels were increased at week 1; all matrix protein mRNA levels except col IV were increased at week 2; but only tenascin, laminin and col IV mRNA levels remained elevated at three weeks. Plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metallo-proteinases (TIMP)-1 mRNA levels were significantly increased at two weeks. During the three weeks there was no change in urokinase, stromelysin or TIMP-3 mRNA levels. These results suggest that both increased matrix protein synthesis and altered matrix remodeling/degradation contribute to the final interstitial fibrogenic process in rats with protein-overload proteinuria. Mø, one of the sources of TGF-beta 1, infiltrate the interstitium by complex recruitment mechanisms which may depend in part on osteopontin, ICAM-1 and VCAM-1 expression.

These recommendations are intended to provide primary care physicians with a useful reference when they are faced with a young child or teenager who presents with proteinuria, whether this is mild and asymptomatic or more severe, leading to nephrotic syndrome.

Joubert syndrome (JS) is an autosomal recessive multisystem disease characterized by cerebellar vermis hypoplasia with prominent superior cerebellar peduncles (the "molar tooth sign" [MTS] on axial magnetic resonance imaging), mental retardation, hypotonia, irregular breathing pattern, and eye-movement abnormalities. Some individuals with JS have retinal dystrophy and/or progressive renal failure characterized by nephronophthisis (NPHP). Thus far, no mutations in the known NPHP genes, particularly the homozygous deletion of NPHP1 at 2q13, have been identified in subjects with JS. A cohort of 25 subjects with JS and either renal and/or retinal complications and 2 subjects with only juvenile NPHP were screened for mutations in the NPHP1 gene by standard methods. Two siblings affected with a mild form of JS were found to have a homozygous deletion of the NPHP1 gene identical, by mapping, to that in subjects with NPHP alone. A control subject with NPHP and with a homozygous NPHP1 deletion was also identified, retrospectively, as having a mild MTS and borderline intelligence. The NPHP1 deletion represents the first molecular defect associated with JS in a subset of mildly affected subjects. Cerebellar malformations consistent with the MTS may be relatively common in patients with juvenile NPHP without classic symptoms of JS.