Impaired Renal Autoregulation Research Articles

Altered gap junctional communication and renal haemodynamics in Zucker fatty rat model of type 2 diabetes

We examined the link between altered gap junctional communication and renal haemodynamic abnormalities in diabetes in studies performed on Zucker lean (ZL) and the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes. The abundance of connexin (Cx) 37, 40 and 43 was assessed by western blot and immunohistochemistry. Renal haemodynamics was characterised with GAP peptides, which are Cx mimetics, to inhibit gap junctions as a probe in both strains. ZDF rats exhibited higher plasma glucose, 8-epi-prostaglandin F2α excretion, renal plasma flow and GFR than ZL rats. In ZDF rat kidney phosphorylation of Cx43 was enhanced compared with that in ZL rats. Immunohistochemical study revealed that the density of abundance of Cx37 in renin-secreting cells was significantly reduced in ZDF rats. Although renal autoregulation was markedly impaired in ZDF rats, it was preserved in ZL rats. GAP27 for Cx37,43 and for Cx40 impaired renal autoregulation in ZL rats, but failed to induce further alterations in renal autoregulation in ZDF rats. Our findings indicate that ZDF rats have glomerular hyperfiltration with impaired autoregulation. They also demonstrate enhanced phosphorylation of Cxs and reduced production of Cxs in ZDF rat kidney, especially of Cx37 in renin-secreting cells. Finally, our data suggest that an impairment of gap junctional communication in juxtaglomerular apparatus plays a role in altered renal autoregulation in diabetes.

Telmisartan improves endothelial dysfunction and renal autoregulation in Dahl salt-sensitive rats

Hypertensive vascular disorders are characterized by endothelial dysfunction. Loss of renal autoregulation causes glomerular hypertension. However, the relationship between the autoregulatory response and glomerular damage has not been well examined. We examined the contributions of uncoupled endothelial nitric oxide synthase (eNOS) in hypertensive renal disease, and the relationship between the degree of autoregulation impairment and glomerular injury. We also investigated the effects of telmisartan on eNOS coupling and renal autoregulation. Male Dahl salt-sensitive hypertensive (DS) rats (14-week old) fed an 8% salt diet were used to examine endothelial dysfunction and impaired renal autoregulation caused by glomerular hypertension. Some DS rats were treated with telmisartan (3.0 mg kg(-1) day(-1)), an angiotensin receptor blocker, for 2 weeks. Increased superoxide production and decreased nitric oxide production, as detected by fluorescent indicator perfusion methods, were observed in the glomeruli and arterioles of hypertensive DS rats. Telmisartan improved the imbalance of superoxide and nitric oxide in the glomeruli and arterioles. Decreased serum tetrahydrobiopterin levels and coupled eNOS seen in the DS rat kidney were improved with telmisartan treatment. The endothelial relaxation reaction was impaired in DS rat aortic arteries. Autoregulatory capacity in response to step changes in perfusion pressure was also impaired in DS rat kidney. Treatment with telmisartan improved these abnormalities. Endothelial dysfunction in the glomeruli and impaired renal autoregulation, which may cause glomerular sclerosis, were observed in DS rat kidney. Telmisartan treatment improves these dysfunctions in hypertensive renal disease.

Hypertension management in patients with chronic kidney disease

Hypertension is one of the major risk factors for the development and progression of chronic kidney disease. The loss of renal function leads to impaired renal autoregulation and renders the kidney vulnerable to the damaging effects of uncontrolled hypertension. Mounting evidence indicates that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers slow the progression of chronic kidney disease through effects beyond lowering blood pressure. Studies are needed to determine whether high doses of the single agent or combination therapy is most effective in providing renal protection. Urinary protein excretion is a useful tool for monitoring and titrating therapy to maximize renal protection. Changes in the serum creatinine concentration and hyperkalemia are complications of antihypertensive therapy in patients with chronic kidney disease that can be successfully managed to allow continued use of renin-angiotensin blockade.

Renal Consequences of Prostaglandin Inhibition in Heart Failure

Prostaglandins are products of intracellular arachidonate metabolism via the cyclooxygenase pathways. In the kidney, prostaglandins are modulators of afferent arteriole autoregulation. In diminished effective intravascular volume, vasodilatory prostaglandins reduce afferent arteriolar resistance, helping to maintain overall glomerular filtration. In subjects who have a low perfusion state, as in congestive heart failure, arthrosclerosis, hepatorenal syndrome, and cirrhosis, impaired renal autoregulation occurs, predisposing to kidney injury. Adverse effects of prostaglandin inhibition include acute kidney injury, hyperkalemia, hypertension, and edema. Hypertension and edema can occur because prostaglandins play an important role in renal regulation of salt and water balance. This review summarizes the renal consequences of using prostaglandin inhibitors in subjects who have congestive heart failure.

Management of Acute Renal Failure in the Elderly Patient

Numerous anatomical and functional changes occurring in the aging kidney lead to reduced glomerular filtration rate, lower renal blood flow and impaired renal autoregulation. The elderly are especially vulnerable to the development of renal dysfunction and in this population acute renal failure (ARF) is a common problem. ARF is often iatrogenic and multifactorial; common iatrogenic combinations include pre-existing renal dysfunction and exposure to nephrotoxins such as radiocontrast agents or aminoglycosides, use of NSAIDs in patients with congestive cardiac failure and use of ACE inhibitors and diuretics in patients with underlying atherosclerotic renal artery stenosis. The aetiology of ARF is classically grouped into three categories: prerenal, intrinsic and postrenal. Prerenal ARF is the second most common cause of ARF in the elderly, accounting for nearly one-third of all hospitalized cases. Common causes can be grouped into true volume depletion (e.g. decreased fluid intake), decreased effective blood volume (e.g. systemic vasodilation) and haemodynamic (e.g. renal artery stenosis, NSAID use). Acute tubular necrosis (ATN) is the most common cause of intrinsic ARF and is responsible for over 50% of ARF in hospitalized patients, and up to 76% of cases in patients in intensive care units. ATN usually occurs after an acute ischaemic or toxic event. The pathogenesis of ATN involves an interplay of processes that include endothelial injury, microvascular flow disruption, tubular hypoxia, dysfunction and apoptosis, tubular obstruction and trans-tubular back-leak. Vasculitis causing ARF should not be missed as this condition is potentially life threatening. The likelihood of a postrenal cause for ARF increases with age. Benign prostatic hypertrophy, prostatic carcinoma and pelvic malignancies are all important causes. Early identification of ARF secondary to obstruction with renal imaging is essential, and complete or partial renal recovery usually ensues following relief of the obstruction.A comprehensive medical and drug history and physical examination are all invaluable. Particular attention should be paid to the fluid status of the patient (skin turgor, jugular venous pressure, lying and standing blood pressure, urine output). Urinalysis should be performed to detect evidence of proteinuria and haematuria, which will aid diagnosis. Fractional excretion of sodium and urine osmolality may be measured but the widespread use of diuretics in the elderly gives rise to unreliable results. Renal imaging, usually ultrasound scanning, is routinely performed for assessment of renal size and to exclude urinary obstruction. In some cases, renal biopsy is necessary to provide specific diagnostic information. The general principles of managing ARF include treatment of life-threatening features such as shock, respiratory failure, hyperkalaemia, pulmonary oedema, metabolic acidosis and sepsis; stopping and avoiding administration of nephrotoxins; optimization of haemodynamic and fluid status; adjustment of drug dosage appropriate to glomerular filtration rate; early nutritional support; and early referral to nephrologists for diagnosis of ARF cause, timely initiation of dialysis and initiation of specific treatment. The treatment of prerenal and ATN ARF is largely supportive with little evidence of benefit from current pharmacological therapies. Despite advances in critical care medicine and renal replacement therapy, the mortality of ARF has not changed significantly over the last 40 years, with current mortality rates being up to 75%.

Connexins 37 and 40 transduce purinergic signals mediating renal autoregulation

Our previous data indicated that various subtypes of connexin (Cx) were expressed in the juxtaglomerular apparatus. Experiments were performed to characterize the effects on renal autoregulation of specific mimetic peptides that inhibit these Cx subtypes in Wistar-Kyoto rats. Intrarenal infusion of (Cx37,43)GAP27 increased autoregulatory index of renal plasma flow (0.06 +/- 0.05 to 0.47 +/- 0.06, n = 6, P < 0.05) and glomerular filtration rate (GFR; 0.01 +/- 0.07 to 0.49 +/- 0.07, P < 0.05). The additional administration of 8-cyclopentyl- 1,3-dipropylxanthine (CPX) produced a further elevation of autoregulatory index of RPF (0.86 +/- 0.07, P < 0.05) and GFR (0.88 +/- 0.09, P < 0.05), compared with (Cx37,43)GAP27 alone. However, the addition of pyridoxal-phosphate-6-azophenyl-2,4-disulfonic acid (PPADS) to (Cx37,43)GAP27 did not. Combined treatment with CPX and PPADS markedly worsened autoregulatory index of RPF (0.04 +/- 0.10 to 0.81 +/- 0.06, n = 6 P < 0.01) and GFR (0.05 +/- 0.08 to 0.79 +/- 0.05, P < 0.01). (Cx40)GAP27 induced similar changes to (Cx37,43)GAP27. Renal autoregulation was preserved in the presence of (Cx43)GAP26. Our results indicate that the inhibition of gap junction impaired renal autoregulation. Furthermore, the present data provide evidence that both adenosine and purinergic receptors contribute to glomerular autoregulation. Finally, our findings suggest that gap junctions, at least in part, transduce purinergic signals mediating renal autoregulation.

Increased blood pressure variability and impaired renal autoregulation in obese Zucker rats

Increased blood pressure variability and impaired renal autoregulation in obese Zucker rats

Synergistic QTL interactions between Rf-1 and Rf-3 increase renal damage susceptibility in double congenic rats

The FHH (fawn-hooded hypertensive) rat is a model of hypertension-associated chronic kidney damage. Five interacting quantitative trait loci (QTLs), named Rf-1-Rf-5, determine the high renal susceptibility. The aim of the present study was to investigate a possible interaction between Rf-1 and Rf-3. Differences in renal susceptibility between ACI (August x Copenhagen Irish) controls, Rf-1A and Rf-3 single congenics, and Rf-1A+3 double congenic rats were assessed using four different treatments: two-kidney control (2K), 2K plus N(omega)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension (2K+L-NAME), unilateral nephrectomy (UNX), and UNX plus L-NAME-induced hypertension (UNX+L-NAME). Proteinuria (UPV) and systolic blood pressure (SBP) were assessed after 6, 12, and 18 weeks, while the incidence of glomerulosclerosis (%FGS) was determined at the end of the experiment. In a separate experiment, renal autoregulation was assessed in 13-15-week old 2K rats of all four strains. Compared to ACI rats, small increases in renal susceptibility were found in Rf-1A and Rf-3 single congenics following 2K+L-NAME, UNX, and UNX+L-NAME treatments. However, in the Rf-1A+3 double congenics, a major increase in renal susceptibility was found with all four treatments. Both Rf-1A and Rf-1A+3 congenic rats had an impaired renal autoregulation. In contrast, the Rf-3 had a normal autoregulation, similar to that of the ACI rat. These findings indicate that Rf-1 and Rf-3 alone slightly increase the susceptibility to the development of renal damage. However, a synergistic interaction between these two QTLs markedly enhances renal susceptibility. In contrast to the Rf-1 region, the Rf-3 region does not carry genes influencing renal autoregulation.

Cardiometabolic Syndrome and Chronic Kidney Disease: What Is the Link?

The term metabolic syndrome or cardiometabolic syndrome describes the clustering of several cardiovascular and renal risk factors, including type 2 diabetes mellitus, central obesity, hypertension, and dyslipidemia. Over the past 15 years, several studies have examined the association between the metabolic/cardiometabolic syndrome or its central component, insulin resistance, with the presence of elevated urine albumin excretion. Intrarenal changes associated with the cardiometabolic syndrome result in elevated glomerular filtration rate, impaired pressure natriuresis, endothelial dysfunction related to changes in nitric oxide and, hence, impaired renal autoregulation and enhanced chronic inflammation. The aforementioned changes that occur in the cardiometabolic syndrome all contribute to the development of renal injury. While this review focuses on the epidemiology and mechanisms associated with vascular/renal injury, it must be remembered that prevention and treatment of kidney disease require a multifactorial approach. Weight loss through diet and exercise can reverse many of these pathophysiologic adaptations. Pharmacologic intervention should be aimed at achieving guideline goals and include insulin sensitizers to aid in tight glycemic control, lipid control, blockade of the renin-angiotensin-aldosterone system for blood pressure reduction, and anti-inflammatory therapies.

Disturbances in Renal Autoregulation and the Susceptibility to Hypertension-Induced Chronic Kidney Disease

The risk of developing chronic kidney disease in the setting of hypertension varies among patient populations. Black hypertensive patients have an increased risk of developing hypertension-induced chronic kidney disease even after taking into account socioeconomic factors. There is evidence to suggest that the kidney is intrinsically more susceptible to the damaging effects of hypertension in black patients. This susceptibility can be traced to disturbances in the way the kidney autoregulates. Impaired renal autoregulation may be the renal manifestation of a more widespread abnormality in endothelial function. Other conditions that can impair renal autoregulation and add to the risk of chronic kidney disease include low birth weight, obesity, insulin resistance, hyperuricemia, and hypercholesterolemia. To minimize the risk of chronic kidney disease in patients with impaired renal autoregulatory capability, strict blood pressure control is required. There is indirect evidence that blocking the renin-angiotensin system may improve renal autoregulation.

Progressive renal and cardiovascular disease: Optimal treatment strategies

Progressive renal and cardiovascular disease: Optimal treatment strategies

Impaired Renal Autoregulation: Implications for the Genesis of Hypertension and Hypertension-Induced Renal Injury

In summary, autoregulation of the renal vasculature provides a mechanism by which renal function is maintained relatively constant despite variations in systemic blood pressure. This system also provides a means for changes in blood pressure to occur without causing inappropriate alterations in urinary NaCl excretion. Alterations in the autoregulatory response can have clinical consequences. Increased activity of the TGF mechanism may be causally related to the development of some forms of hypertension. Decreased activity of TGF or an impaired myogenic response may help explain the increased susceptibility that certain patient groups exhibit toward hypertension-induced renal injury. The aggressive treatment of hypertension in patients with impaired renal autoregulation may be associated with an increase in the serum creatinine concentration. As long as this increase is neither excessive nor progressive, physicians should not be dissuaded from trying to achieve newly established blood pressure goals.

Interaction between nitric oxide and renal myogenic autoregulation in normotensive and hypertensive rats

Blood pressure fluctuates continuously throughout life and autoregulation is the primary mechanism that isolates the kidney from this fluctuation. Compared with Wistar rats, Brown Norway (B-N) rats display impaired renal myogenic autoregulation when blood pressure fluctuation is increased. They also are very susceptible to hypertension-induced renal injury. Because blockade of nitric oxide augments myogenic autoregulation in Wistar rats, we compared the response of the myogenic system in B-N rats to nitric oxide blockade with that of other strains [Wistar, Sprague-Dawley, Long-Evans, spontaneously hypertensive (SHR)]. Renal blood flow dynamics were assessed in isoflurane anesthetized rats before and after inhibition of nitric oxide synthase by Lomega-nitro-arginine methyl-ester (L-NAME, 10 mg/kg, iv). Under control conditions, myogenic autoregulation in the B-N rats was weaker than in the other strains. Myogenic autoregulation was not augmented after L-NAME administration in the SHR, but was augmented in all the normotensive rats. The enhancement was significantly greater in B-N rats so that after L-NAME the efficiency of autoregulation did not differ among the strains. The data suggest that nitric oxide is involved in the impaired myogenic autoregulation seen in B-N rats. Furthermore, the similarity of response in Wistar, Long-Evans, and Sprague-Dawley rats suggests that modulation by nitric oxide is a fundamental property of renal myogenic autoregulation.

Class differences in the effects of calcium channel blockers in the rat remnant kidney model

Controversy persists as to the existence of class differences between calcium channel blockers (CCBs) in their ability to provide renoprotection and as to potential mechanisms involved. Rats with 5/6 renal ablation were left untreated or received diltiazem, verapamil, or felodipine after the first week, and the relationship between continuous radiotelemetrically measured blood pressure (BP) and glomerulosclerosis (GS) was assessed at seven weeks. Additionally, the effects of these CCBs on renal autoregulation and hypertrophy were examined at three weeks after renal ablation. Although an excellent linear correlation was observed between the average BP levels and GS in all groups (r = 0.75 to 0.84, P < 0.01), significant protection was not achieved with any of the CCBs, but for different reasons. The antihypertensive effects of diltiazem were not sustained beyond the second week. Verapamil significantly reduced the average BP (144 +/- 4 mm Hg vs. 181 +/- 8 in untreated rats) but shifted the slope of the relationship between BP and GS (increase in percentage GS/mm Hg increase in average systolic BP) to the left (x intercept 121 vs. 144 mm Hg for untreated rats, P < 0.01) so that GS was not reduced. Felodipine also significantly reduced the average BP (144 +/- 3 mm Hg) and shifted the slope to the left (x intercept 123 mm Hg), but additionally made the slope steeper (2.3 +/- 0.5 vs. 0.82 +/- 0.2 in untreated rats). Because of these differing effects on the relationship between BP and GS, the rank order of GS for any given BP elevation was as follows: felodipine > verapamil > diltiazem = untreated. Felodipine, but not verapamil or diltiazem, caused additional impairment of the already impaired renal autoregulation in untreated rats, thereby explaining its adverse effects on GS. By contrast, the adverse effects of verapamil on GS were attributable to the greater amplitude of BP fluctuations that was observed in the verapamil-treated rats such that for any given average BP, these rats were exposed to greater peak pressures as compared with the other groups. None of the CCBs had a significant effect on glomerular hypertrophy. These class differences between CCBs in their relative impact on systemic BP profiles, renal autoregulation, and glomerular pressure transmission may have clinically significant implications and may account for the variable glomeruloprotection that has been observed with these agents in both experimental models and in humans.

Intraglomerular hypertension and hyperfiltration due to impaired renal autoregulation in the fawn-hooded hypertensive (FHH) rat

Intraglomerular hypertension and hyperfiltration due to impaired renal autoregulation in the fawn-hooded hypertensive (FHH) rat

Acute Na + ,K + -ATPase Inhibition With Bufalin Impairs Pressure Natriuresis in the Rat

Although it has been reported that Na+,K+-ATPase inhibition with bufalin induces acute and chronic hypertension in the rat, the mechanisms mediating this response are unclear. To examine the role of the kidney in this process, glomerular filtration rate, renal blood flow, and pressure natriuresis were determined in rats treated with bufalin or vehicle during changes in renal perfusion pressure. Mean arterial pressure increased from 123 +/- 4 to 149 +/- 3 mm Hg (P < .05) after 40 minutes of intravenous bufalin and remained at this level. In control rats, glomerular filtration rate was well autoregulated. In bufalin-treated rats, glomerular filtration rate fell with decreasing renal perfusion pressure. Glomerular filtration rate autoregulatory index was greater in bufalin-treated than control rats (P < .05). Renal blood flow showed a similar pattern. Urine flow and sodium excretion were less in bufalin-treated than control rats at equivalent renal perfusion pressures. The slope of the line describing the relation between urine flow and renal perfusion pressure was greater (P < .05) in control than bufalin-treated rats. Similarly, the slope of the line relating sodium excretion to renal perfusion pressure was greater (P < .05) in control than bufalin-treated rats. Thus, acute increases in blood pressure during Na+, K+-ATPase inhibition are associated with impaired renal autoregulation and pressure natriuresis. This effect may be important in chronic hypertension associated with Na+,K+-ATPase inhibition in the rat.

Prostaglandins do not mediate impaired autoregulation or increased renin secretion in remnant rat kidneys.

The rat remnant kidney model, produced by approximately five-sixths reduction in functional renal mass, is characterized by renal vasodilation, impaired autoregulation, and increased activity of the renin-angiotensin system. The present studies were designed to investigate the role of vasodilatory prostaglandins (PGs) in the altered hemodynamics in the remnant kidney. Four weeks post-ablation, renal blood flow (RBF), was significantly higher in rats fed a standard protein (SP) diet (n = 16) compared with low-protein-fed (LP) rats (n = 7) (6.2 +/- 0.6 vs. 3.7 +/- 0.5 ml/min; P < 0.01), autoregulation was impaired in SP rats [autoregulation index (AI) 1.0 +/- 0.1 (SP) vs. 0.2 +/- 0.1 (LP); P < 0.05], and renin secretory rates were significantly increased in SP rats both during the basal state [24 +/- 7 (SP) vs. 2 +/- 1 (LP) ng.ml-1 x h-1 x min-1; P < 0.05] and after reduction in renal perfusion pressure [110 +/- 29 (SP) vs. 16 +/- 7 (LP); P < 0.05]. Indomethacin administration (5 mg/kg bolus + 5 mg.kg-1 x h-1 infusion) in additional SP rats (n = 11) decreased RBF from 7.4 +/- 1.1 to 5.9 +/- 1.0 ml/min (P < 0.05) without improvement in autoregulation (AI = 1.1 +/- 0.3). Renin basal secretory rate and response to decreased renal perfusion pressure were not altered by indomethacin. These data suggest that PGs contribute to the renal vasodilation in the rat remnant kidney model, but they do not mediate the impaired renal autoregulation or the increased renin release.