Role Of Glomerular Capillary Hypertension

Of the glomerular hemodynamic determinants of hyperfiltration, the available evidence suggests that glomerular capillary hypertension plays the key role in progression of renal injury. Long-term protection against albuminuria and glomerular sclerosis was obtained in normotensive diabetic rats by angiotensin converting enzyme inhibitor (ACEI) therapy in doses which modestly lowered systemic blood pressure, but selectively normalized PGC, without affecting the supranormal SNGFR and QA [26]. Studies in a variety of experimental models, including diabetes, have consistently shown that interventions which control glomerular capillary hypertension are associated with marked slowing of the development of structural injury [115].

Until recently, little was known of the exact mechanism(s) by which glomerular capillary hypertension eventuates in structural injury. Recently, innovative new techniques using a variety of in vitro systems have been developed to address this question. These studies postulate that glomerular hemodynamic factors modify the growth and activity of glomerular component cells, inducing the elaboration or expression of cytokines and other mediators, which then stimulate mesangial matrix production and promote structural injury. For instance, increased shear stress on endothelial cells enhances activity of such mediators as endothelin [116], NO [117,118], transforming growth factor-B [119], and several cellular adhesion molecules [120,121] and modulates release of platelet derived growth factor [122,123]. Altered hemodynamics also influence mesangial cells: it has been postulated that expansion of the glomerular capillaries, and stretching of the mesangium in response to hypertension, might translate high PGC into increased mesangial matrix formation [124]. Evidence for this mechanism comes from observations in microperfused rat glomeruli, in which increased hydraulic pressure was associated with increased glomerular volume; and in cultured mesangial cells, where cyclic stretching resulted in enhanced synthesis of protein, total collagen, collagen IV, collagen I, laminin, fibronectin, and transforming growth factor-B (TGF-B)[125-128]. Of particular relevance to diabetes, the accumulation of extracellular matrix caused by any degree of mechanical strain is aggravated in a milieu of high glucose concentration [128].

Additionally, growing mesangial cells under pulsatile conditions has been reported to stimulate PKC, calcium influx, and proto-oncogene expression [129], and Ang II receptor and angiotensinogen mRNA levels [125], as well as altered extracellular matrix protein processing enzymes [130,131]. Mediators of oxidant stress are induced by shear stress in vascular smooth muscle cells [132], as well as mechanical stretch in proximal tubular cells [133]. More evidence comes from the recent finding that application of pressure (comparable to elevated glomerular pressures in vivo) enhances mesangial cell matrix synthesis in cultured cells [134]. Finally, application of stress reduces glomerular epithelial cell podocyte differentiation and [135] and induces F-actin reorganization [136], representing another pathway of cellular injury. Given these new techniques, the cellular and molecular mechanisms by which glomerular hyperfiltration and hypertension leads to structural injury are in process of being elucidated.

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