Effetti dell’acidosi metabolica da cloruro di ammonio sul GFR in un modello murino


Chronic metabolic acidosis (CMA) is a known complication of chronic renal failure (CRF) and is involved in the pathogenesis of other IRC-related complications, such as altered bone metabolism, protein turn-over, the endocrine system and cardio-vascular system. Recent data suggest that the AMC plays a role in the progression of the IRC. However, the molecular mechanisms of renal damage AMC-related are not perfectly clear. In murine models the AMC due to tubular and glomerular hypertrophy, and is associated with a reduction in protein catabolism. Similarly in humans, the AMC experimentally induced is associated with a reduction in tubular proteolysis, with probable morpho-functional consequences.


The aim of the study was to evaluate the effects of metabolic acidosis on the structure and renal function, and secondly to identify the pathways involved.


Metabolic acidosis was induced experimentally in a murine model by the addition of NH4Cl to the drinking water. For 1, 2, 3, 7, 15, 21 days of treatment were carried out: EGA, GFR measurement by inulin clearance, renal Immunohistochemistry and RT-PCR.


The arterial blood gas analysis data showed a significant reduction of the bicarbonataemia already after 1 day of treatment. After 3 days the bicarbonataemia increases, while remaining at levels significantly lower than controls until the end of treatment (Fig. 1).

The GFR was increased from baseline to 1-3 days of treatment, an expression of glomerular hyperfiltration. Subsequently, the GFR progressively decreases, reaching very low levels after 3 weeks of treatment (Fig. 2).

The blue areas, in the renal cortex section highlighted by the use of the trichrome staining, identify the deposition of extracellular material during the renal failure progression (Fig. 3).

Performing amplification by RT-PCR of transcripts encoding for the Type III Collagen, it’s evident the increasing of mRNA levels of collagen during the administration of the acid load (Fig. 4).


The present work demonstrates for the first time that the metabolic acidosis induced by NH4Cl administration causes glomerular hyperfiltration in acute phase and progressive reduction in GFR subsequently associated with increased Type III Collagen synthesis, like other processes such as those associated to kidney damage, arterial hypertension and diabetes mellitus. Remain to be elucidated the molecular pathways involved.


The discovery of the metabolic pathways involved in renal damage the AMC product widen the possibility of using different drugs by administration of alkali, burdened by the need of multi and daily subministration and the high dose required to achieve the therapeutic target. In addition, the comparison of metabolic pathways activated by acidosis with those induced in the course of diabetic nephropathy or renal-hypertensive angiosclerosi provides the ability to identify biological processes (and therapeutic targets) common and cause-specific.