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

Understanding the nature of renal disease progression

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.

Interplay between proliferation and differentiation within the myogenic lineage

Diseases of muscle that are caused by pathological interactions between muscle and the immune system are devastating, but rare. However, muscle injuries that involve trauma and regeneration are fairly common, and inflammation is a clear feature of the regenerative process. Investigations of the inflammatory response to muscle injury have now revealed that the apparently nonspecific inflammatory response to trauma is actually a complex and coordinated interaction between muscle and the immune system that determines the success or failure of tissue regeneration.

/pdf/regulation-of-muscle-growth-and-regeneration-by-the-immune-22vud9geiv.pdf

Regulation of muscle growth and regeneration by the immune system

The role of polypeptide growth factors in promoting muscle differentiation is uncharacterized. We have used a fusing skeletal muscle cell line, C2, to examine the endogenous expression of one peptide, insulin-like growth factor II (IGF-II), and its receptor during differentiation. The synthesis of IGF-II is low during proliferation of myoblasts; IGF-II mRNA can be detected only through use of a highly sensitive solution-hybridization assay. Competition binding studies reveal that the IGF-II receptor is similarly nonabundant in myoblasts. During differentiation IGF-II mRNA rises rapidly. A nearly 4-fold increase is seen within 16 hr of onset of the differentiation process, and levels are 25 times higher than those in myoblasts by 96 hr, when myotubes have formed and muscle-specific alpha-actin mRNAs are synthesized. IGF-II accumulates in conditioned culture medium with similar kinetics. The expression of IGF-II receptors on the cell surface increases almost 6-fold 24 hr after the onset of differentiation and remains high. These studies suggest that IGF-II and its receptor are coordinately regulated during myogenic differentiation in C2 cells and that IGF-II may be an autocrine factor for skeletal muscle.

https://www.pnas.org/content/pnas/86/5/1543.full.pdf

Coordinate expression of insulin-like growth factor II and its receptor during muscle differentiation.

Tubular catabolism of albumin is associated with the release of an inflammatory lipid

https://www.ajkd.org/article/S0272-6386(01)17552-9/pdf

Jenny Levis Sadow

Papers

Coordinate expression of insulin-like growth factor II and its receptor during muscle differentiation.

Tubular catabolism of albumin is associated with the release of an inflammatory lipid

Hepatocyte growth factor inhibits apoptosis after ischemic renal injury in rats.