Diabetic nephropathy (DN) is the primary cause of chronic kidney disease. Despite therapeutic advances, DN remains the principal cause of mortality in diabetic patients (Dugbartey, 2017).

Renin–angiotensin system (RAS) has been classically involved in the progression of diabetic cardiovascular disease. A chronically activated endocrine or paracrine RAS is considered as a principal contributor to the pathophysiology of end-organ damage in diabetes mellitus (DM), including the DN (Urushihara and Kagami, 2017). As a result, therapeutic drugs for DN are targeting mostly the renin–angiotensin–aldosterone system (Yacoub and Campbell, 2015).

Although debate remains, the therapeutic drugs for DN currently consist mainly of angiotensin II (Ang II) receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) used for their antihypertensive and antiproteinuric measures (Bhattacharjee et al., 2016). Direct renin inhibitors (DRIs) acting on rate-limiting enzyme of the RAS offered probability of a greater inhibition of the system so as to have better therapeutic outcomes in patients with DN (Parving et al., 2008). The rationale for developing renin inhibitors was as follows: renin is the first and rate-limiting step in RAS cascade (low renin concentration in the pM range), renin has high specificity for angiotensinogen (little side effects anticipated), ACEIs and ARBs result in incomplete RAS suppression [reactive rise in plasma renin activity (PRA), “escape” mechanism, and other products of RAS (e.g., Ang1–7, AIII, and AIV)] (Wood and Close, 1996; Nussberger et al., 2002; Stanton, 2003). However, larger trials of the DRI aliskiren in combination with an ACE inhibitor or ARB in patients with DN did not reduce cardiovascular or renal outcomes (Parving et al., 2012).

Plasma renin activity played a central role as a pharmacological biomarker for drug development, safety, and dosing in the research and development (R&D) of DRIs such as remikiren, enalkiren, zankiren, and aliskiren. Generally, DRIs induced rapid reductions of 65–95% PRA (Lambers Heerspink et al., 2009). PRA has been used in the estimation of the extracellular volume, because this correlates inversely with PRA (Juncos, 2013). Hence, Brunner et al. (1972) categorized hypertensive patients by their volume status using PRA levels. Augmented PRA levels represent a risk factor of cardiovascular disease (Alderman et al., 1991; Parving et al., 2009). Whereas several pathologies are associated with an augmented PRA, DM and associated DN apparently are not.

The therapeutic effects of RAS inhibitors may be important depending on the pathological activation of endocrine and/or tissue RAS (Gasparo et al., 2013; de Alencar Franco Costa et al., 2015). For instance, disease conditions with low baseline PRA levels reduced the treatment efficacy of DRIs (Stanton et al., 2009). Few reviews on DRI for DN as therapeutic target discussed PRA as an outcome measure (Abassi et al., 2009; Rafiq et al., 2011; Jagadeesh et al., 2012). These reviews document that PRA is reduced in DM with or without DN.

Early studies described hyporeninemia or low-renin state as a characteristic state of circulatory RAS in DM patients with or without DN (Sousa et al., 2016). Our and other studies (de Alencar Franco Costa et al., 2015; Sousa et al., 2016) evidencing a diabetes-induced low-renin status may indicate that a DRI is not always effective in treating DN. Therefore, the purpose of this study was to examine and synthesize the existing literature on DRI effects on PRA in DN. Literature search included studies that investigated DRIs such as remikiren, enalkiren, zankiren, or aliskiren in DN.

The present study shows that a low number of preclinical and clinical studies with DRIs as monotherapy or add-in therapy in DN assessed PRA. Only two randomized controlled studies reported renoprotective effects in DN associated with a significant reduction in PRA.

Of eight publications identified to report DRI effects on urinary albumin in DN (Parving et al., 2008, 2012; Persson et al., 2009, 2010, 2011, 2012a,b; Abe et al., 2012), only three clinical studies presented data on PRA. All three involved patients with both DM and HTN. As aliskiren does not lower blood pressure in hypertensive patients with low PRA (Sealey and Laragh, 2009), Jagadeesh et al. (2012) suggested that “it may be useful to dichotomize RAAS-related pathologic syndromes into ones associated with high renin (some HTN, any HTN after diuretic treatment), where aliskiren appears to be quite effective, and low-renin” (like diabetes), where aliskiren is of uncertain value. Indeed, in the AVOID study (Parving et al., 2008), a prespecified subset of 133 (22%) patients from a total of 599 patients was identified with a significant decrease in PRA by aliskiren (Persson et al., 2012a). The study of Uresin et al. (2007) that reported a significant reduction in 24-h ambulatory blood pressure presented PRA data on 32% of the total patients recruited in the DRI study group. As such, important information that could lead to patient stratification could be learned from disclosing the PRA data from the ALTITUDE study (Parving et al., 2012).

Dual therapy of the DRI aliskiren with ACEI or ARBs was commonly investigated in patients with HTN, heart failure, and diabetes with or without proteinuria. It is conceptualized that the antihypertensive efficacy of aliskiren is increased when adding ACEIs, ARBs, or diuretics, which produce a reactive increase in PRA. Indeed, aliskiren in combination with ACEIs or ARBs showed significant blood pressure and proteinuria reductions than monotherapy alone in phase II trials with hypertensive patients with or without DM (Persson et al., 2009), reviewed by Şen et al. (2013). Clinical trials that studied the combination of aliskiren and ACEI or ARBs and involved patients with DM include Pool 2007, ALOFT 2008, ALLAY 2009, AVANTE GARDE 2010, VANTAGE 2010, and ASPIRE 2011. These studies were systematically reviewed by Harel et al. (2012). They were not designed to investigate outcomes in DM patients. A meta-analysis of 13,395 patients with diabetes showed no benefit from the addition of aliskiren to standard medical therapy (Zheng et al., 2017).

Finding a preclinical experimental model for DM and DN was challenged by the high selectivity of aliskiren for human renin compared with renin from other species (IC50 values [50% inhibitory concentrations]: human 0.6, marmoset 2, rat 80, dog 7) (Wood et al., 2003). The first studies of DRI on an experimental DM model used the STZ-induced DM in high-renin hypertensive (mRen-2)27 rats (Kelly et al., 2007; Feldman et al., 2008). However, this DM model cannot consider the phenotype alterations as primarily induced by DM because these rats genetically activated renin production. Four studies reported DRI effects on DN of db/db mice (Table 2). Another study on db/db mice showed no significant differences in their PRA compared to control db/m mice (Gallo et al., 2016).

Experimental models investigated for proof-of-concept efficacy of aliskiren in DN were db/db mice for type 2 DM (T2DM) and STZ mice (DBA/2J and C57BL/6J strains) for type 1 DM (T1DM). The db/db mice are characterized by T2DM, elevated systolic blood pressure, obesity, and hyperlipidemia. They develop T2DM with high plasma levels of insulin and glucose at weeks 9–10 of age (Forbes and Cooper, 2013). The main outcomes studied for DN, including increased albumin excretion and glomerular pathology, are very similar between mouse lines with T1DM or T2DM and humans with DM (Azushima et al., 2017).

Locally activated synthesis and activity of renin have been identified in kidney and other organs in different pathologies (Bader et al., 2001). Such organs where a local tissue RAS has been postulated include the heart, blood vessels, kidney, brain, adipose tissue, adrenal gland, pancreas, liver, reproductive system, lymphatic tissue, placenta, and eyes (Nehme et al., 2019). Diseases where chronically activated local tissue RAS has been identified include HTN, atherosclerosis, heart failure, cardiac hypertrophy and fibrosis, chronic kidney disease, and glaucoma (Ames et al., 2019; Nehme et al., 2019). An increase in local production of active angiotensins could be through the classical renin–ACE pathway or through alternative pathways (Ferrario et al., 2014). Translational proof-of-concept studies shall distinguish the enzymes involved in these RAS pathways in order to identify therapeutic targets. For instance, we have demonstrated in a proof-of-concept study that renin might be a therapeutic target in glaucoma (Wang et al., 2012). This does not seem to be the case in DN where both preclinical and clinical proof-of-concept studies indicate that DN is associated with a low-renin state. In Table 3B, we summarized the clinical studies that described hyporeninemia in DM, with the first report dated year 1973. These studies indicate that hyporeninemic hypoaldosteronism is underdiagnosed in DM (Sousa et al., 2016). Several mechanisms have been suggested as responsible for the reduction in renin release in patients with DM, including juxtaglomerular injury, autonomic dysfunction, and primary increase in renal salt retention with volume expansion (Phelps et al., 1980; Sousa et al., 2016). The first experimental studies of RAS in DM used alloxan-DM or STZ-DM rat models (Table 3A). Preclinical evidence for an activated renal RAS in DM is suggested by our and others studies on increased synthesis and urinary secretion of renal angiotensinogen (Zimpelmann et al., 2000; Saito et al., 2009; de Alencar Franco Costa et al., 2015; Lee et al., 2017) (Figure 2 shows urinary angiotensinogen as a potential biomarker). STZ-induced DM in rats caused a 69% increase of Ang II in the renal interstitial fluid, which was decreased 27% by aliskiren (6 weeks’ treatment) (Matavelli et al., 2012). As aliskiren did not normalize the DM-increased renal interstitial fluid Ang II, alternative Ang II-forming pathways might have been activated. One candidate enzyme that may take over the renin activity in kidney to activate the local Ang II production is cathepsin L. Cathepsin L was identified as a potential sex-specific biomarker for renal damage by the Actelion group (Bauer et al., 2011). Cathepsin L appears to be importantly involved in the development of albuminuria and renal damage in early experimental DN (Garsen et al., 2016) (Figure 2). Angiotensinogen may be degraded by cathepsins including cathepsin L, which may degrade angiotensinogen (Watanabe et al., 1989). As cathepsin L can be involved in the pathogenesis of DN through several mechanisms, targeting with suitable antagonists may hold promises for therapeutic interventions (Kumar and Anders, 2016). PRA is not a good indicator of local RAS activity as measure circulating production of angiotensin I, where ACE, alternative Ang II-forming enzymes, and Ang II might be increased in the local tissue. Although PRA is a pharmacological efficacy biomarker for aliskiren and has been considered as an outcome measure in DM, the effects of renin inhibitors on local tissue RAS are not easily demonstrable in clinical studies because there are no available biomarkers for local RAS activation. Studies on urinary peptidome might lead to the characterization of biomarkers for local renal RAS activation, such as cathepsin L or D (Krochmal et al., 2017).

Very few studies addressed the PRA as the outcome measure of DRI treatment effect in DN. Therefore, for a more successful translational research, specific patient population where DRI treatment is effective in DN should be identified. Additional well-designed randomized controlled trials (RCTs) using PRA as a marker for patient stratification and randomization may be warranted.

OB and LC contributed to the conception and design of the study. MD, AB, GP, OB, and LC analyzed and interpreted the data. MD, AB, GP, OB, and LC drafted the manuscript. All authors provided critical revision of the article.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.