Cellular responses to protein overload: key event in renal disease progression

Insight into the mechanisms underlying the progression of chronic proteinuric nephropathies has attracted the interest of the renal community in the last two decades. Systemic hypertension, proteinuria, cytokines and growth factors, and reactive oxygen species have all been implicated. Reviewed here are the determinants of tubulointerstitial injury; the focus is on protein ultrafiltration and reabsorption, which ultimately contribute, by activating fibrogenic mechanisms in tubular cells, to renal scarring.

Protein overloading of proximal tubular cells--a well-documented consequence of exuberant protein ultrafiltration--differentially regulates transcription of NF-kappaB-dependent and NF-kappa-B-independent genes. This forms endothelin-1, cytokines and chemokines; all of these, being secreted toward the basolateral compartment of tubular epithelial cells, foster local recruitment of mononuclear cells. Autocrine pathways of activation of tubular epithelial cells contribute to interstitial injury and fibrosis. Albumin endocytosis in proximal tubular cells triggers events that include protein kinase C-dependent generation of reactive oxygen species, nuclear translocation of NF-kappaB, and activation of mitogen-activated protein kinase. In-vivo evidence that proteinuria activates transcription factors, including NF-kappaB, and overexpression of chemokine and fibrogenic cytokines is also available.

Proteinuria incites a multitude of inflammatory and fibrogenic mediators, all of which contribute to renal scarring. Specific antagonism of multiple injurious pathways might help to arrest, or even reverse, the progression of renal damage.