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The physiological and pathological processes of the kidney as a whole can now be analyzed with a molecular precision at a genomic-scale. Using massively parallel cDNA microarray technology, the mRNA expression of thousands of genes can be quantified simultaneously. The advantages of microarray analyses include the ability to examine the interaction of several genes or the entire genome in a single experiment. Bioinformatics approaches such as data mining through mathematical condensation of the massive gene expression profiles are essential for elucidating molecular and biological logic underlying gene expression programs. Genes that encode similar protein components are often coordinately regulated. Recent application of gene expression profiling to the normal human renal cortical tissue, experimental in vitro and in vivo models has shown that cellular activation is accompanied by changes of hundreds of genes in parallel. The databases of gene expression emerging from these studies will be used to interpret the pathological changes in gene expression that accompany a variety of human renal diseases.

Na+/H+ exchangers (NHE) play a critical role in many cellular and transport processes in the inner medullary collecting duct (IMCD). Morphologically, the IMCD is divided into the outer (IMCD1), middle (IMCD2), and inner (IMCD3) segments. The inner, IMCD3 segment contains only one cell type, the IMCD cell, which is distinct in ultrastructure and in function from the principal and intercalated cells that are present in other portions of the IMCD. NHEs constitute a gene family containing several isoforms (NHE1, NHE2, NHE3, NHE4 and NHE5) which possess distinct characteristics and serve specialized functions. To understand the molecular basis of NHE-related processes in the IMCD, it is critical to know the molecular identity of the NHEs in this tubule segment. The purpose of the present study was to identify the NHE isoforms present and their polar distribution in IMCD3. Applying the reverse transcription-polymerase chain reaction (RT-PCR) technique to IMCD3 (obtained from distal 50% of inner medulla) of mouse and rat kidneys, we found that NHE1, NHE2 and NHE4, but not NHE3 were expressed in both species. The polar localization of NHE in IMCD3 was examined in tubules isolated from rats and perfused in vitro with HEPES-buffered solutions under isotonic conditions. pHi was measured by BCECF fluorescence. Na+-dependent, amiloride-inhibitable pHi recovery from cell acidification (consistent with NHE) was detected in the basolateral, but not the apical, membrane of IMCD3. We conclude that NHE1, NHE2 and NHE4, but not NHE3, are present in both the mouse and rat IMCD3. Functionally, NHE is limited to the basolateral membrane. Additional studies are needed to determine the physiological roles and regulation of basolateral NHE isoforms in this tubule segment.

Left ventricular hypertrophy (LVH) is a generalized adaptation to altered myocardial load. Hypertension induces significant increases in ventricular IGF-I gene expression that occur coordinately with development of LVH. To test whether IGF-I promotes initiation of LVH, we examined ventricular IGF-I mRNA content in spontaneously hypertensive rats (SHRs) treated with antihypertensive drugs that limit or permit LVH.Prehypertensive SHRs were left untreated or treated with enalapril, nifedipine, or hydralazine. Systolic blood pressure (SBP), hypertrophy index (ventricular weight/body weight), and ventricular IGF-I mRNA levels were examined 2, 4, and 6 weeks after beginning therapy in the experimental groups.Systolic blood pressure reached hypertensive levels after 2 weeks in untreated animals, and was controlled in the treated animals. The hypertrophy index in untreated animals was significantly elevated at 4 weeks. By 6 weeks, the hypertrophy indices of both the enalapril- and nifedipine-treated groups were significantly lower than that of the untreated group. In contrast, the hypertrophy index of the hydralazine-treated animals remained comparable to that of the untreated animals. By 4 weeks, IGF-I mRNA levels in the enalapril- and nifedipine-treated groups were significantly lower than those in the untreated and hydralazine-treated groups.We conclude that: (1) antihypertensive drugs that reduce LVH blunt ventricular IGF-I mRNA content; and (2) the hemodynamic effects of antihypertensives may be dissociated from their ability to promote or limit a hypertrophic response. The clear association of LVH with ventricular IGF-I mRNA content suggests that IGF-I is an important determinant of ventricular growth. Our data also suggest that angiotensin-converting enzyme inhibitors and calcium channel blockers may reduce LVH by inhibiting cardiac IGF-I gene expression.

Studies in animals suggest that hepatocyte growth factor (HGF) is an important mediator of kidney development, compensatory growth and tubule repair following acute injury, however, evidence for HGF action in human renal disease is scant. To determine whether increased renal production of HGF occurs in man, urine HGF excretion rate was measured in normals and in patients with a variety of acute and chronic renal diseases. Urine samples were collected from 9 healthy individuals, 25 individuals with acute tubular necrosis (ATN), 20 individuals with chronic glomerular disease, 9 patients with polycystic kidney disease and 10 individuals with severe chronic renal failure not yet receiving renal replacement therapy. Samples were initially frozen and then HGF content measured by ELISA and factored for creatinine concentration measured by autoanalyzer. Detectable but low levels of HGF were found in the urine of normals and in patients with chronic glomerular or polycystic disease. Levels were also not increased in patients with advanced, chronic renal insufficiency. In contrast, a marked increase in urine HGF was observed in patients with acute renal failure. In addition, HGF excretion tended to correlate with disease severity as higher levels were observed in patients with oliguric ATN. Urine HGF levels declined to control values in patients recovering from ATN, generally within one week. These findings are consistent with a role for HGF in promoting tubule cell proliferation, differentiation and recovery from acute tubular injury in man.

Hypertension is common in patients with renal disease and, when uncontrolled, accelerates the rate of progression to end stage renal failure. There is considerable evidence that antihypertensive therapy can slow the rate of decline in kidney function in these patients. However, controversy exists regarding the mechanisms by which antihypertensive agents prevent kidney damage as well as the relative utility of different classes of drugs. This paper will focus on a series of studies, including several conducted in our laboratory, in which the impact of antihypertensive agents on kidney structure and function have been examined in experimental models of progressive kidney failure. Taken together, these studies suggest that most drugs that reduce systemic blood pressure will also lessen kidney damage, albeit to varying degrees and by different mechanisms.

The number of patients developing end-stage renal disease (ESRD) as a consequence of hypertension is increasing and accounts for 25% of new cases of ESRD in the United States. However, the diagnosis of hypertensive ESRD is one of exclusion and no pathologic data corroborate this classification. Undoubtedly, these patients suffer from a variety of diseases, including accelerated hypertension and atherosclerotic disease of the large arteries. Also included are patients with an undiagnosed primary renal disease. The prevalence of these conditions in the hypertensive population is unknown. It is also proposed that mild to moderate hypertension can lead to ESRD. In support of this view, early investigators noted that nephrosclerosis was correlated with hypertension and/or left ventricular hypertrophy. More recently, in the Hypertension Detection and Follow-up Program, renal function was found to decline in some patients despite treatment. Data from the Baltimore Longitudinal Study of Aging indicate that the rate at which creatinine clearance declines with aging is correlated with blood pressure. A recent retrospective study reported that serum creatinine increased significantly in approximately 15% of treated hypertensive patients. However, in none of these studies was the presence of intrinsic renal disease definitively excluded. Furthermore, although an increase in serum creatinine or decline in clearance has been reported, progression to end-stage renal disease has not been documented. Therefore, additional studies are necessary to determine the frequency with which essential hypertension leads to end-stage renal disease.

The RK, DS, and UNX SHR rats are related models of progressive renal disease characterized by the presence of severe systemic hypertension and reduction in renal mass. In these models, glomerular injury is related to increased glomerular pressure and to kidney and glomerular hypertrophy. As summarized in Table 1, administration of a calcium antagonist reduces the prevalence of glomerular sclerosis in all three models. Calcium antagonists have many effects that might tend to reduce renal injury. Similar to the ACE inhibitors, they may reduce PGC, although a protective effect has been observed in some models despite persistence of marked glomerular capillary hypertension. Calcium antagonists also appear to inhibit compensatory renal growth. The observation that these drugs lessen injury in experimental hypertension has important implications for the treatment of patients with hypertension and renal disease. However, widespread use of calcium antagonists specifically to prevent kidney damage should await the results of controlled clinical trials.

Recent evidence suggests that calcium channel blockers have specific effects on renal hemodynamics in patients with hypertension and may also slow the progression of chronic renal failure. When these agents are studied in vitro, their predominant effect is to reverse afferent arteriolar vasoconstriction induced by catecholamines or angiotensin II. Because efferent resistance may remain high, glomerular filtration rate rises while renal blood flow remains low. The effects in vivo are less consistent. In human hypertension, calcium channel blockers lower renal resistance and may raise both renal blood flow and glomerular filtration rate. In experimental models of chronic renal disease, calcium channel blockers slow the progression of renal damage; however, variable effects on renal hemodynamics have been found. Other factors implicated in the progression of renal damage, including compensatory renal hypertrophy, platelet aggregation, and calcium deposition, may also be favorably influenced by these agents. Recent studies suggest that calcium channel blockers may have similar protective effects in patients with hypertension and chronic renal disease.

A major problem for patients with kidney disease is that most chronic renal diseases progress to endstage renal failure. Studies in experimental models of hypertension and renal insufficiency suggest that progressive glomerular sclerosis may be the long-term consequence of functional and structural adaptations of the kidney to a moderate loss of filtration capacity. In a number of settings, sclerosis has been related to the presence of an elevated glomerular capillary hydraulic pressure. A growing body of evidence also supports the hypothesis that kidney hypertrophy and glomerular hypertrophy constitute independent risk factors for glomerular sclerosis. Recent studies suggest that calcium antagonists can reduce glomerular injury in experimental hypertension. Renal protection may be related to the ability of these agents to reduce glomerular pressure and/or inhibit compensatory renal growth.

Although intraluminal nutrition presumably maintains small intestinal mass by direct contact with the epithelial cells, hormonal or neurovascular elicited by feeding may play an indirect role. In order to test for the presence of indirect factors, Thiry- Vella fistulae were created from the proximal small intestine of two groups of rats. The bypassed gut of a group of rats receiving an elemental diet intravenously was compared to a second group receiving the same diet by intragastric infusion. After 1 week, there was significantly greater (P less than 0.01) gut weight, mucosal weight, DNA content, and protein content of both the gut in continuity and tje bypassed gut of intragastric infused rats. Total sucrase activity was also greater (P less than 0.01) in intragastric fed rats, and this was due to both a greater protein content and specific activity (P is less than 0.05) of the gut in continuity and to the greater protein content of the bypassed gut. Serum gastrin levels were similar (P less than 0.05) in both groups, suggesting that gastrin may not play a role in initiating the differences reported. This study suggests that intraluminal nutrition maintains the small intestinal epithelial population in part, indirectly, by unidentified hormonal or neurovascular stimuli.