Glomerular hypertension, abnormal glomerular growth, and progression of renal diseases

Agnes B Fogo

Vanderbilt University Medical Center, Nashville, Tennessee, USA

Correspondence: Agnes B. Fogo, M.D., MCN C3310, Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, 37232, USA. E-mail:Agnes.Fogo@mcmail.vanderbilt.edu

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Abstract

Glomerular hypertension, abnormal glomerular growth, and progression of renal diseases. The development and progression of sclerosis is determined by complex interactions of many mechanisms, including direct hemodynamic actions, modulation of glomerular cell injury, and growth factor actions. The interplay of these factors determines the balance of cell growth and proliferation versus cell death by necrosis or apoptosis, and the balance of matrix accumulation versus degradation. Sclerosis may even be reversed when therapies inhibit these mechanisms and augment matrix degradation processes, both by directly increasing proteolytic activity and by down-regulating inhibitors of matrix degradation. We will focus in this review on the roles of glomerular hemodynamics and growth in the progression of renal diseases.

Keywords:

glomerular cell injury, proliferation, chronic renal disease

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Glomerular hypertension and sclerosis

Hypertension accelerates progression of chronic renal disease in humans, whether it results from, or causes, the renal disease. Glomerular pressure can be modulated differentially from systemic blood pressure. The potential impact of these local glomerular hemodynamic changes on sclerosis has been extensively studied in the Munich-Wistar rat because it has superficial glomeruli, which can be directly punctured to measure glomerular blood pressures and flows. The remnant kidney model, where 5/6 of the total renal parenchyma is removed, results in progressive hypertension, proteinuria and matrix expansion, culminating in focal segmental glomerulosclerosis, mimicking key aspects of progressive injury in humans^1,2,3. Anderson et al⁴ showed superior protection against progressive sclerosis in this model with angiotensin I-converting enzyme inhibitor (ACEI) compared to nonspecific antihypertensive treatment. Although systemic pressures were normalized with both interventions, glomerular pressures were decreased only by ACEI, and remained high with nonspecific therapy. This led to the postulate of increased capillary pressure as a key mediator of progressive sclerosis in a self-perpetuating vicious cycle, whereby loss of nephrons due to sclerosis further increased flow and pressures in remaining glomeruli, thus augmenting and perpetuating injury. We performed serial micropuncture studies in the same model to investigate whether hemodynamic derangement predicted the ultimate severity of sclerosis in those same punctured glomeruli. At sacrifice, these same micropunctured glomeruli were identified, processed and histologically assessed for sclerosis. The sclerosis indices for the individual glomeruli were then correlated with either maximum single nephron glomerular filtration rate (GFR), glomerular pressure, or average values for these parameters as assessed by repeated micropuncture in these same glomeruli over the preceding weeks⁵. There was no correlation between the degree of total sclerosis and these hemodynamic variables in individual glomeruli, suggesting additional nonhemodynamic factors contribute to sclerosis.

Clinical data have shown superior efficacy on progression of ACEI over nonspecific antihypertensive therapy, not attributable to blood pressure effects⁶. Cell culture studies indeed show that angiotensin II (Ang II) can directly induce mesangial cell hypertrophy and/or proliferation, depending on culture conditions, and increase extracellular matrix (ECM) production⁷. We therefore examined the possibilities that ACEI in doses higher than those required to lower increased blood pressure might have further beneficial effects⁸. The severity of glomerulosclerosis was assessed by renal biopsy at 8 weeks after 5/6 nephrectomy. Animals were then divided into groups that received no treatment, usual antihypertensive dose of ACEI, or a four-fold higher dose of ACEI. Both systemic and glomerular pressures were normalized by both ACEI doses, with no further hemodynamic effects at the higher dose. Progression of sclerosis was seen in all untreated animals from biopsy to autopsy. Progression of sclerosis was significantly ameliorated in animals receiving the normal ACEI dose. Remarkably, sclerosis was even further ameliorated and even regressed in response to the four-fold higher ACEI dose, with less sclerosis at autopsy than at biopsy 4 weeks previously in three of the five rats. An angiotensin type 1 receptor antagonist (AIIRA) was similarly effective, achieving regression in half of the rats. This regression was associated with marked inhibition of plasminogen activator inhibitor-1 (PAI-1) protein expression (see below) (abstract; Nakamura et al, J Am Soc Nephrol 10:665A, 1999). Similar reversal of sclerosis by ACEI or AIIRA was observed in the nonhypertensive puromycin aminonucleoside model of glomerulosclerosis by us and others^9,10.

The impact of hemodynamic vs. other factors on progressive injury at the single glomerular level was investigated in the ureteral diversion model¹¹. The ureter of one kidney was diverted into the peritoneum with partial ablation of the contralateral kidney, resulting in marked glomerular hyperperfusion and hyperfiltration and increased glomerular pressure. These changes, however, were accompanied by only minimal glomerulosclerosis, and only minimal glomerular enlargement occurred. In contrast, in the 5/6 nephrectomy model, marked glomerular enlargement occurred and was closely associated with glomerulosclerosis. Glomerular enlargement and sclerosis were also closely correlated at an individual glomerular level in a biphasic distribution, with positive correlation of glomerular enlargement and sclerosis at early phases of sclerosis (i.e., up to 50% of the tuft involved) and a negative correlation as the glomeruli became smaller as progressive sclerosis developed until obsolescence occurred¹². The ACEI effect in ameliorating sclerosis in the remnant kidney model was associated with inhibition of glomerular growth, while maintaining the correlation of sclerosis and glomerular size. Of note, ACEI was not equally effective at all stages of fibrosis; progressive deterioration continued in glomeruli with more advanced sclerosis despite ACEI, whereas progression was inhibited in glomeruli at earlier stages of sclerosis. These findings suggest that different mechanisms of sclerosis were active among the heterogeneously affected glomeruli, with different potentials for response to treatment and remodeling. These data indicate that abnormal glomerular growth is associated with, and may be a marker of mechanisms leading to sclerosis. These experiments also indicate that hyperfiltration alone is insufficient to induce pathogenic glomerular hypertrophy and subsequent sclerosis.

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