Early potential impairment of renal sensory nerves in streptozotocin-induced diabetic rats: role of neurokinin receptors.

BACKGROUND: Electrophysiological studies in the mammalian kidney have identified two major classes of sensory receptors of the afferent renal nerves; chemoreceptors (CR) and mechanoreceptors (MR). The localization of calcitonin gene-related peptide (CGRP) and substance P (SP) in these renal pelvic sensory neurons provides an anatomical basis for a possible functional interaction between the two neuropeptides and SP receptor. The present study was performed to examine the possible changes in the responsiveness of renal sensory SP and CGRP receptors in rats with streptozotocin (STZ)-induced diabetes mellitus. Due to the crucial role of renal pelvic SP and CGRP receptors in the activation of renal sensory neurons by various stimuli, we examined whether the responsiveness of MR or CR activation and the dorsal root ganglia content of neuropeptides and neurokinin 1 receptors (NK(1)R) were altered in diabetic rats compared with non-diabetic rats. METHODS: Afferent renal nerve activity (ARNA) was recorded from the peripheral portion of the cut end of one renal nerve branch placed on a bipolar silver wire electrode. T(13) dorsal root ganglia (DRG) immunoreactivity was performed to NK(1)R, SP and CGRP. RESULTS: The results of the current study confirmed that the stimulation of renal MR and CR elicited a renorenal reflex response, and that the renal pelvic administration of SP and CGRP increased ipsilateral ARNA and contralateral urinary sodium excretion with no changes in arterial pressure. We also found a decrease in NK(1)R expression followed by an increase in SP and CGRP levels in the DRG of diabetic rats. The ARNA response, produced by renal pelvic MR and CR stimulation, was found to be significantly attenuated in the STZ-induced diabetic model. Conclusions. These data may indicate a compensatory synthesis and/or abnormal axonal delivery of neurokinins from the cell body to synaptic portions of the neuron as the underlying reason for attenuated ARNA in renal sensory neurons of diabetic rats.

Expression of renin-angiotensin system signalling compounds in maternal protein-restricted rats: effect on renal sodium excretion and blood pressure.

BACKGROUND: Intrauterine growth restriction due to low maternal dietary protein during pregnancy is associated with retardation of foetal growth, renal alterations and adult hypertension. The renin-angiotensin system (RAS) is a coordinated hormonal cascade in the control of cardiovascular, renal and adrenal function that governs body fluid and electrolyte balance, as well as arterial pressure. In the kidney, all the components of the renin-angiotensin system including angiotensin II type 1 (AT1) and type 2 (AT2) receptors are expressed locally during nephrogenesis. Hence, we investigated whether low protein diet intake during pregnancy altered kidney and adrenal expression of AT1(R) and AT2(R) receptors, their pathways and if the modified expression of the RAS compounds occurs associated with changes in urinary sodium and in arterial blood pressure in sixteen-week-old males' offspring of the underfed group. METHODS: The pregnancy dams were divided in two groups: with normal protein diet (pups named NP) (17% protein) or low protein diet (pups LP) (6% protein) during all pregnancy. RESULTS: The present data confirm a significant enhancement in arterial pressure in the LP group. Furthermore, the study showed a significantly decreased expression of RAS pathway protein and Ang II receptors in the kidney and an increased expression in the adrenal of LP rats. The detailed immunohistochemical analysis of RAS signalling proteins in the kidney confirm the immunoblotting results for both groups. The present investigation also showed a pronounced decrease in fractional urinary sodium excretion in maternal protein-restricted offspring, compared with the NP age-matched group. This occurred despite unchanged creatinine clearance. CONCLUSIONS: The current data led us to hypothesize that foetal undernutrition could be associated with decreased kidney expression of AT(R) resulting in the inability of renal tubules to handle the hydro-electrolyte balance, consequently causing arterial hypertension.

Impact of taurine supplementation on blood pressure in gestational protein-restricted offspring: Effect on the medial solitary tract nucleus cell numbers, angiotensin receptors, and renal sodium handling.

OBJECTIVE: The current study considers changes of the postnatal brainstem cell number and angiotensin receptors by maternal protein restriction (LP) and LP taurine supplementation (LPT), and its impact on arterial hypertension development in adult life. METHODS AND RESULTS: The brain tissue studies were performed by immunoblotting, immunohistochemistry, and isotropic fractionator analysis. The current study shows that elevated blood pressure associated with decreased fractional urinary sodium excretion (FENa) in adult LP offspring was reverted by diet taurine supplementation. Also, that 12-day-old LP pups present a reduction of 21% of brainstem neuron counts, and, immunohistochemistry demonstrates a decreased expression of type 1 angiotensin II receptors (AT1R) in the entire medial solitary tract nuclei (nTS) of 16-week-old LP rats compared to age-matched NP and LPT offspring. Conversely, the immunostained type 2 AngII (AT2R) receptors in 16-week-old LP nTS were unchanged. CONCLUSION: The present investigation shows a decreased FENa that occurs despite unchanged creatinine clearance. It is plausible to hypothesize an association of decreased postnatal nTS cell number, AT1R/AT2R ratio and FENa with the higher blood pressure levels found in taurine-deficient progeny (LP) compared with age-matched NP and LPT offspring.

Involvement of renal corpuscle microRNA expression on epithelial-to-mesenchymal transition in maternal low protein diet in adult programmed rats.

Prior study shows that maternal protein-restricted (LP) 16-wk-old offspring have pronounced reduction of nephron number and arterial hypertension associated with unchanged glomerular filtration rate, besides enhanced glomerular area, which may be related to glomerular hyperfiltration/overflow and which accounts for the glomerular filtration barrier breakdown and early glomerulosclerosis. In the current study, LP rats showed heavy proteinuria associated with podocyte simplification and foot process effacement. TGF-ß1 glomerular expression was significantly enhanced in LP. Isolated LP glomeruli show a reduced level of miR-200a, miR-141, miR-429 and ZEB2 mRNA and upregulated collagen 1α1/2 mRNA expression. By western blot analyzes of whole kidney tissue, we found significant reduction of both podocin and nephrin and enhanced expression of mesenchymal protein markers such as desmin, collagen type I and fibronectin. From our present knowledge, these are the first data showing renal miRNA modulation in the protein restriction model of fetal programming. The fetal-programmed adult offspring showed pronounced structural glomerular disorders with an accentuated and advanced stage of fibrosis, which led us to state that the glomerular miR-200 family would be downregulated by TGF-ß1 action inducing ZEB 2 expression that may subsequently cause glomeruli epithelial-to-mesenchymal transition.

Early changes of hypothalamic angiotensin II receptors expression in gestational protein-restricted offspring: effect on water intake, blood pressure and renal sodium handling.

The current study examines changes in the postnatal hypothalamic angiotensin receptors by maternal protein restriction (LP), and its impact on in uteri programming of hypertension in adult life. The data show that LP male pup body weight was significantly reduced when compared to that of control (NP) pups. Also, immunoblotting analysis demonstrated a significantly decreased expression of type 1 AngII receptors (AT1R) in the entire hypothalamic tissue extract of LP rats at 12 days of age compared to age-matched NP offspring. Conversely, the expression of the type 2 AngII (AT2R) receptors in 12-day- and 16-week-old LP hypothalamus was significantly increased. The current data show the influence of central AngII administration on water consumption in a concentration-dependent fashion, but also demonstrate that the water intake response to AngII was strikingly attenuated in 16-week-old LP. These results may be related to decreased brain arginine vasopressin (AVP) expression appearing in maternal protein-restricted offspring. The present investigation shows an early decrease in fractional urinary sodium excretion in maternal protein-restricted offspring. The decreased fractional sodium excretion was accompanied by a fall in proximal sodium excretion and occurred despite unchanged creatinine clearance. These effects were associated with a significant enhancement in arterial blood pressure in the LP group, but the precise mechanism of these phenomena remains unknown.