The possibility that proteinuria may accelerate kidney disease progression to end-stage renal failure has received support from the results of increasing numbers of experimental and clinical studies. Evidence indicating that this process occurs through multiple pathways, including induction of tubular chemokine expression and complement activation that lead to inflammatory cell infiltration in the interstitium and sustained fibrogenesis, is reviewed. Macrophages are prominent in the interstitial inflammatory infiltrate. This cell type mediates progression of renal injury to the extent that macrophage numbers in renal biopsy predict renal survival in patients with chronic renal disease. Chemoattractants and adhesive molecules for inflammatory cells are upregulated by excess ultrafiltered protein load of proximal tubular cells via activation of NF-kappaB-dependent and NF-kappaB-independent pathways. This mechanism is a potential target for therapeutic approaches, as shown by beneficial effects of manipulations with inhibitory molecules of NF-kappaB activation or of chemokine receptors in experimental studies. Targeting complement synthesis or activation in proximal tubule might offer novel therapeutic opportunities. Finally, proximal tubular cell receptors for uptake of plasma proteins that are under investigation may provide activation signals on excess tubular protein handling.

How Does Proteinuria Cause Progressive Renal Damage

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

Molecular basis of renal fibrosis.

https://www.kidney-international.org/article/S0085-2538(17)30819-0/pdf

Renal tubule injury: a driving force toward chronic kidney disease.

Diabetic nephropathy ensues from events involving earliest changes in the glomeruli and podocytes, followed by accumulation of extracellular matrix in the mesangium. Postulated mechanisms include roles for vascular endothelial growth factor (VEGF), produced by podocytes and contributing to enhanced excretion of urinary albumin and recruitment/activation of inflammatory cells, and transforming growth factor-β (TGF-β), elicited largely from mesangial cells and driving production of extracellular matrix. RAGE, a receptor for advanced glycation endproducts (AGEs) and S100/calgranulins, displays enhanced expression in podocytes of genetically diabetic db/db mice by age 13 weeks. RAGE-bearing podocytes express high levels of VEGF by this time, in parallel with enhanced recruitment of mononuclear phagocytes to the glomeruli; events prevented by blockade of RAGE. By age 27 weeks, soluble RAGE-treated db/db mice displayed diminished albuminuria and glomerulosclerosis, and improved renal function. Diabetic homozygous RAGE null mice failed to develop significantly increased mesangial matrix expansion or thickening of the glomerular basement membrane. We propose that activation of RAGE contributes to expression of VEGF and enhanced attraction/activation of inflammatory cells in the diabetic glomerulus, thereby setting the stage for mesangial activation and TGF-β production; processes which converge to cause albuminuria and glomerulosclerosis.

RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy.

. Leukocyte trafficking from peripheral blood into affected tissues is an essential component of the inflammatory reaction to virtually all forms of injury and is an important factor in the development of many kidney diseases. Advances in the past few years have highlighted the central role of a family of chemotactic cytokines called chemokines in this process. Chemokines help to control the selective migration and activation of inflammatory cells into injured renal tissue. Chemokines and their receptors are expressed by intrinsic renal cells as well as by infiltrating cells during renal inflammation. This study summarizes the in vitro and in vivo data on chemokines and chemokine receptors in renal diseases with a special focus on potential therapeutic effects on inflammatory processes.

Chemokines, Chemokine Receptors, and Renal Disease: From Basic Science To Pathophysiologic and Therapeutic Studies

Cytokines play a pivotal role in synthesis and deposition of extracellular matrix in chronic renal failure (CRF). The proinflammatory properties of monocyte chemoattractant protein (MCP)-1 make it an ideal candidate cytokine for the production of interstitial inflammation in CRF. To investigate the possible role of proteinuria in inducing proximal tubular (PT) MCP-1, MCP-1 mRNA levels were measured by Northern blot and reverse transcription PCR in confluent monolayers of PT cells in primary culture in media containing a variety of proteins. PT cells produced MCP-1 mRNA in response to bovine serum albumin (BSA), delipidated BSA (dBSA; 0.5 to 30 mg/ml), holotransferrin, and apotransferrin (1 to 8 mg/ml). Unstimulated PT cells expressed very low levels of MCP-1 mRNA, detectable by reverse transcription PCR but not by Northern blot. The expression of MCP-1 mRNA reached a peak (sixfold greater than control) within 4 h of exposure to dBSA and was maintained for at least 24 h with continued exposure. Removal of dBSA from the media led to a rapid decline in MCP-1 mRNA expression. dBSA-induced MCP-1 expression was inhibited by lysine, an inhibitor of protein uptake, and reproduced by dBSA purified by gel and size-selective filtration. dBSA influenced MCP-1 expression at the level of transcription and probably translation, as evidenced by abrogation of MCP-1 by actinomycin D and superinduction with the protein synthesis inhibitor cycloheximide. The concentration of MCP-1 protein in response to dBSA added to the apical surface of PT cells was 2.4-fold greater in basolateral than in apical media, indicating basolateral secretion of MCP-1 protein. In summary, PT cell MCP-1 mRNA and protein expression are upregulated by albumin and transferrin, in concentrations similar to those of proteinuric urine. This effect could explain the link between proteinuria and interstitial inflammation in CRF.

/pdf/induction-of-monocyte-chemoattractant-protein-1-in-proximal-1564yid5f4.pdf

Induction of monocyte chemoattractant protein-1 in proximal tubule cells by urinary protein.

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Induction of monocyte chemoattractant protein-1 in proximal tubule cells by urinary protein.