Glomerular pathology and the progression of chronic kidney disease

Structural studies of the glomerulus, largely undertaken in animal models, have informed our understanding of the progression of chronic kidney disease (CKD) for decades. A fundamental tenet of that understanding is that a loss of podocytes underlies progression in many or most cases of progressive CKD. Recent attempts have been made to reconcile earlier findings from glomerular physiology (the primacy of glomerular capillary hypertension in causation of secondary glomerular sclerosis) with structural findings and have suggested a more detailed model of the mechanisms underlying podocyte detachment as viable cells. A new appreciation of the main locus of mechanical challenges to the podocyte (in the filtration slit) may both explain the renoprotective action of some current therapies and help to suggest novel therapeutic strategies.

Mechanical strain increases SPARC levels in podocytes: implications for glomerulosclerosis

Glomerular capillary hypertension is a final common pathway to glomerulosclerosis. Because podocyte loss is an early event in the development of glomerulosclerosis, it is logical that the deleterious effects of glomerular capillary hypertension involve podocyte injury. Yet, the mechanisms by which elevated intraglomerular pressure is translated into a maladaptive podocyte response remain poorly understood. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein activated in various disease states of the podocyte and accelerates renal injury, as evidenced by the milder course of experimental diabetic nephropathy in SPARC-null mice compared with diabetic SPARC wild-type mice. Accordingly, we tested the hypothesis that mechanical strain activates SPARC in podocytes and thus is a putative mediator of podocyte injury in states of intraglomerular capillary hypertension. Conditionally immortalized mouse podocytes were subjected to 10% cyclical stretch while nonstretched cells served as controls. SPARC levels were measured in whole cell lysate and cell media. Immunostaining was performed for SPARC in an experimental model of glomerular capillary hypertension. Our results demonstrate cyclical stretch of podocytes markedly increased SPARC levels in cell lysate, through activation of p38, as well as secreted SPARC. Relevance was shown by demonstrating increased podocyte staining for SPARC in the uninephrectomized spontaneously hypertensive rat. In conclusion, we have made the novel observation that mechanical forces characteristic of states of glomerular capillary hypertension lead to increased levels of SPARC in podocytes. We speculate that the increase in SPARC may be maladaptive and lead to a progressive reduction in podocyte number, thus fueling the future development of glomerulosclerosis.

Glomerular hemodynamic effects of late pregnancy in rats with experimental membranous glomerulonephropathy.

In these studies, the Fx1A model of accelerated, passive Heymann nephritis was used to produce membranous glomerulonephropathy. Female rats were studied at 7 wk after the administration of the Fx1A antibody either in the virgin state or in late pregnancy. The goals of these experiments were to determine whether preexisting membranous glomerulonephropathy compromises the pregnancy and whether the pregnancy acutely worsens the renal function. Virgin rats with membranous glomerulonephropathy developed massive proteinuria and exhibited glomerular capillary hypertension but without declines in GFR. In late pregnancy, there was no worsening of the proteinuria and glomerular blood pressure fell to normal values. Both afferent and efferent arteriolar resistances increased in pregnant rats with membranous glomerulonephropathy compared with virgins, leading to falls in glomerular plasma flow and single-nephron GFR. There were no histologic abnormalities in the glomeruli of either virgin or late pregnant rats with membranous glomerulonephropathy, and both groups exhibited similar immunoglobulin G and complement deposits. Up to Day 19 (term is 22 days), the pregnancy in rats with membranous glomerulonephropathy appeared uneventful. Thus, this study indicates that the Fx1A model of membranous glomerulonephropathy does not compromise the course of the pregnancy, at least until close to term. Pregnancy lowers glomerular blood pressure in rats with membranous glomerulonephropathy because of both a fall in systemic blood pressure and the atypical renal vasoconstriction, which leads to declines in single-nephron GFR.

Physiological and structural responses to chronic experimental renal allograft injury

Chronic rejection necessitates a return to dialysis or retransplantation for a significant number of patients with renal allografts. Although alloresponses between donor organ and recipient importantly determine this process, the detailed immunologic processes and organ physiology of chronic rejection are unclear; in consequence its mechanism and therapy are uncertain. A model of chronic rejection in the rat was used to examine several facets of this process. Fisher-to-Lewis (F-L), allogeneic, and Lewis-to-Lewis (L-L), syngeneic, renal transplants were performed in nephrectomized recipients. All rats were treated with cyclosporin A (5 mg.kg-1.day-1) for 10 days from the time of grafting. At 6 wk, allogeneically grafted animals had a higher protein excretion rate (F-L, 47 +/- 30 mg/day; L-L, 17 +/- 6 mg/day; P <0.05) and an increase in glomerular capillary pressure (F-L, 69 +/- 5 mmHg; L-L, 58 +/- 8 mmHg; P <0.05) and fractional cortical interstitial volume (F-L, 29.8 +/- 4.3%; L-L, 19.5 +/- 4.0%; P < 0.01). This model of chronic rejection is characterized by glomerular capillary hypertension, proteinuria, and cortical interstitial expansion. Because these findings are also present in other models of chronic renal injury, mechanisms in addition to alloresponses may operate in chronic rejection.

Pathogenesis of glomerular injury in the fawn-hooded rat: early glomerular capillary hypertension predicts glomerular sclerosis.

Fawn-hooded rats spontaneously develop focal and segmental glomerular sclerosis, systemic hypertension, and proteinuria at a young age. Micropuncture and morphological studies were performed in two inbred strains of fawn-hooded rats, FHH and FHL, with different susceptibilities to develop chronic renal failure. FHH rats have higher values for systolic blood pressure and proteinuria and more rapid development of focal and segmental glomerular sclerosis and subsequent chronic renal failure as compared with genetically closely related FHL rats. FHH and FHL strains and a Wistar control strain, WAG, were matched for age and were studied at 16 wk. FHH, FHL, and WAG-old (WAG-O) strains were matched for weight, and the last group was studied at 22 wk. WAG were also matched for weight to a young group of FHH rats (FHH-Y), and these were studied at 8 wk. In comparison with WAG and WAG-O rats, FHH and FHH-Y rats exhibited an increased in mean glomerular capillary hydraulic pressure (WAG, 52 +/- 1 mm Hg; WAG-O, 47 +/- 2 mm Hg; FHH, 60 +/- 2 mm Hg; FHH-Y, 65 +/- 1 mm Hg), whereas values in FHL animals were intermediate (56 +/- 2 mm Hg). No significant differences in glomerular volume were found among groups. Moderate focal and segmental glomerular sclerosis developed in FHH and FHH-Y rats, with values for older FHH rats being significantly greater than those for WAG, WAG-O, and FHL animals. Thus, the genetically determined sensitivity to develop proteinuria, focal and segmental glomerular sclerosis, and chronic renal failure in fawn-hooded rats correlated with early evidence of glomerular capillary hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia ameliorates progressive renal injury in experimental DOCA-salt hypertension.

To explore the role of systemic hematocrit in the vascular adaptations which characterize desoxycorticosterone-salt hypertension, studies were performed in three groups of rats with uninephrectomy, desoxycorticosterone administration, and 1% saline in the drinking water. One group received recombinant human erythropoietin to increase hematocrit, and another group was subjected to phlebotomy and fed a low-iron diet to induce anemia. Control rats exhibited systemic and glomerular capillary hypertension, proteinuria, and substantial glomerular sclerosis at 8 wk. Erythropoietin modestly increased hematocrit and blood pressure and substantially aggravated glomerular capillary pressure, proteinuria, and glomerular sclerosis. In contrast, reduction of hematocrit with a low-iron diet significantly attenuated systemic and glomerular hypertension, proteinuria, and sclerosis. It was concluded that the pace of progression of glomerular injury can be limited by chronic reduction in hematocrit, which effectively ameliorates both systemic and glomerular hypertension in this model of salt-sensitive hypertensive renal disease.